Recent media reports commented about a possible antidiabetics’ misuse issue related to molecules promoted as a weight-loss treatment in non-obese people. We evaluated here available pharmacovigilance misuse/abuse signals related to semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, in comparison to other GLP-1 receptor agonists (albiglutide; dulaglutide; exenatide; liraglutide; lixisenatide; tirzepatide) and the phentermine-topiramate combination. To that aim, we analysed the Food and Drug Administration-FDA Adverse Events Reporting System (FAERS) dataset, performing a descriptive analysis of adverse event reports (AER) and calculating related pharmacovigilance measures, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR). During January 2018-December 2022, a total of 31,542 AER involving the selected molecules were submitted to FAERS; most involved dulaglutide (n=11,858; 37.6%) and semaglutide (n=8,249; 26.1%). In comparing semaglutide vs the remaining nolecules, the AER ‘drug abuse’, ‘drug withdrawal syndrome’, ‘prescription drug used without a prescription’ and ‘intentional product use issue’ respective PRR values were 4.05, 4.05, 3.60 and 1.80 (all<0.01). The same comparisons of semaglutide vs the phentermine-topiramate combination were not associated with any significant differences. To the best of our knowledge, this is the first study documenting the misusing/abusing potential of semaglutide in comparison with other GLP1 analogues and the phentermine-topiramate combination. Current findings will need to be confirmed by further empirical investigations to fully understand the safety profile of those molecules.

Recent media reports commented about a possible antidiabetics’ misuse issue related to molecules promoted as a weight-loss treatment in non-obese people. We here evaluated available pharmacovigilance misuse/abuse signals related to semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, in comparison to other GLP-1 receptor agonists (albiglutide; dulaglutide; exenatide; liraglutide; lixisenatide; tirzepatide) and the phentermine-topiramate combination. To that aim, we analysed the Food and Drug Administration-FDA Adverse Events Reporting System (FAERS) dataset, performing a descriptive analysis of adverse event reports (AER) and calculating related pharmacovigilance measures, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR). During January 2018-December 2022, a total of 31,542 AER involving the selected molecules were submitted to FAERS; most involved dulaglutide (n=11,858; 37.6%) and semaglutide (n=8,249; 26.1%). In comparing semaglutide vs the remaining antidiabetics, the AER ‘drug abuse’, ‘drug withdrawal syndrome’, ‘prescription drug used without a prescription’ and ‘intentional product use issue’ respective PRR values were 4.05, 4.05, 3.60 and 1.80 (all<0.01). The same comparisons of semaglutide vs the phentermine-topiramate combination were not associated with any significant differences. To our best, this is the first study documenting the misusing/abusing potential of semaglutide in comparison with other novel antidiabetics and the phentermine-topiramate combination. Current findings will need to be confirmed by further empirical investigations to fully understand the safety profile of those molecules.

Although various vaccines are now commercially available, they have not been able to stop the spread of COVID-19 infection completely. An excellent strategy to quickly get safe, effective, and affordable COVID-19 treatment is to repurpose drugs that are already approved for other diseases as adjuvants along with the ongoing vaccine regime. The process of developing an accurate and standardized drug repurposing dataset requires a considerable level of resources and expertise due to the commercial availability of an extensive array of drugs that could be potentially used to address the SARS-CoV-2 infection. To address this bottleneck, we created the CoviRx platform. CoviRx is a user-friendly interface that provides access to the data, which is manually curated for COVID-19 drug repurposing data. Through CoviRx, the data curated has been made open-source to help advance drug repurposing research. CoviRx also encourages users to submit their findings after thoroughly validating the data, followed by merging it by enforcing uniformity and integ-rity-preserving constraints. This article discusses the various features of CoviRx and its design principles. CoviRx has been designed so that its functionality is independent of the data it dis-plays. Thus, in the future, this platform can be extended to include any other disease X beyond COVID-19. CoviRx can be accessed at www.covirx.org.

Safe administration of highly cytotoxic chemotherapeutic drugs is a challenging problem in cancer treatment due to the adverse side effects and collateral damage to non-tumorigenic cells. To mitigate these problems, new promising approaches, based on the paradigm of controlled targeted drug delivery (TDD), utilizing drug nanocarriers with biorecognition ability to selectively target neoplastic cells, are being considered in cancer therapy. Herein, we report on the design and testing of a nanoparticle-grid based biosensing platform to aid in the development of new targeted drug nanocarriers. The proposed sensor grid consists of superparamagnetic gold-coated core-shell Fe₂Ni@Au nanoparticles, further functionalized with folic acid targeting ligand, model thiolated chemotherapeutic drug doxorubicin (DOX), and a biocompatibility agent, 3,6,-dioxa-octanethiol (DOOT). The employed dual transduction based on electrochemical and enhanced Raman scattering detection have enabled efficient monitoring of the drug loading onto the nanocarriers, attached to the sensor surface, as well as the drug release under simulated intracellular conditions. The grid’s nanoparticles serve here as the model nanocarriers for new TDD systems under design and optimization. The superparamagnetic properties of the Fe₂Ni@Au NPs aid in nanoparticles’ handling and constructing a dense sensor grid with high plasmonic enhancement of the Raman signals due to the minimal interparticle distance.

Despite innovative advances in anti-infective therapies and vaccine development technologies, community-acquired pneumonia (CAP) remains the most persistent cause of infection-related mortality globally. Confronting the ongoing threat posed by Streptococcus pneumoniae (the pneumococcus), the most common bacterial cause of CAP, particularly to the non-immune elderly, remains challenging due to the propensity of the elderly to develop invasive pneumococcal disease (IPD), together with the predilection of the pathogen for the heart. The resultant development of often fatal cardiovascular events (CVEs), particularly during the first seven days of acute infection, is now recognized as a relatively common complication of IPD. The current review represents an update on the prevalence and types of CVEs associated with acute bacterial CAP, particularly IPD. In addition, it is focused on recent insights into the involvement of the pneumococcal pore-forming toxin, pneumolysin (Ply), in subverting host immune defenses, particularly the protective functions of the alveolar macrophage during early-stage disease. This, in turn, enables extra-pulmonary dissemination of the pathogen, leading to cardiac invasion, cardiotoxicity and myocardial dysfunction. The review concludes with an overview of the current status of macrolide antibiotics in the treatment of bacterial CAP in general, as well as severe pneumococcal CAP, including a consideration of the mechanisms by which these agents inhibit the production of Ply by macrolide-resistant strains of the pathogen.

Cement manufacturing is one of the most energy-intensive industries in the world. Most of the cost of producing cement is accounted by fuel consumption and power expenditures. Thermal power plants are the major source of electricity in Pakistan. But they are not efficient and environmentally friendly. This study simulates four different models for five cement plants of Pakistan on Homer Pro software and compares the optimal solutions based on the net present cost (NPC), levelized cost of electricity (LCOE) and greenhouse gas (GHG) emissions. Model-1 consists of solar panels, electrolyzer, hydrogen tank, hydrogen generator and converter. Model-2 has only a diesel generator and acts as a base case in this study. Model-3 has solar panels and a battery-converter system. In Model-4, diesel generators, solar panels and converters are considered. Based on NPC, the most optimal model is Model-4, having a 0.249 $/KWh LCOE in islanded systems. The NPC and operating costs are US$540 million and US$ 32.5 million per year, respectively, with a 29.80% reduction in CO2 emissions when compared to the base case. Based on GHG emissions, Model-1 and Model-3 are the best models with 0% GHG emissions. Sensitivity analyses is also performed using the parameters of load, inflation rate and discounted rate. The results prove that the proposed hybrid micropower systems (HMS) can sustainably provide electricity for 24 hours a day to the sites under consideration with minimum objectives.

Knowledge about one’s innate health is central to a variety of positive mental health markers. However, men living in prison rarely receive education about how to access these internal resources. As such, this study seeks to replicate and extend emerging data on an innate health intervention. Volunteers from HMP Nottingham, England (n=126) participated in normal prison programming and the intervention group (n=65) received an additional 3-day intensive. The primary question: Does innate health function as a mediator in the same way self-control does within an incarcerated population? We conducted a mediation analysis, tested social desirability bias, and examined the impact of the intervention on crucial variables. This study found higher levels of innate health, self-control, wellbeing, and prosocial behavior and lower levels of aggression in the intervention group as compared to the control group. Importantly, innate health did play a mediating role equivalent to and/or partnering with self-control.

The study explores the potential of Cell-Penetrating Peptides (CPPs) for targeted drug delivery, particularly in anticancer applications. Despite certain drawbacks, such as short duration of action and poor stability in vivo, CPPs show promise when optimized through chemical modification or clever design. Advancements in targeted drug delivery using CPPs, especially for transporting anticancer drugs and imaging reagents, highlight their evolving efficacy. Four different CPP chains (7 alpha, 7 beta, 12 alpha, and 12 beta) and four in-house anticancer lead molecules were considered for the study. The CPPs were modeled and validated for in silico interaction analysis. Targeting proteins crucial in cell growth and signaling pathways, such as ADRM1, PSMD4, CDK1, CDK2, CDK4, CDK6, P53, and EGFR, presents a significant therapeutic opportunity. The in silico molecular interaction analysis involving CPP-conjugated lead molecules and these targets indicates favorable binding affinities, particularly with beta-confirmation 12 and 7 peptide chains. Notably, CPP conjugation enhances interactions without compromising ligand potentiality. This delicate balance emphasizes the role of CPPs in augmenting protein-ligand interactions, suggesting their potential benefits in targeted drug delivery, pending further optimization and experimental validation.

Hyaluronan has been considered in recent years as a potential naturally occurring modifiable scaffold that has the capability to absorb and release drugs over an extended period of time making it suitable as a chemotherapeutic delivery agent. Considering the limited treatment options available in the treatment of glioblastoma, in this review, we discuss the novel utilization of ultra high molecular weight hyaluronan - originally identified as a mechanism for maintaining longevity in the naked mole rat, as both a protective and extracellular matrix optimising scaffold, and a means to deliver therapy in resected brain tumors. The unique properties of this unique form of hyaluronan indicate potential future use in the prevention and treatment of both proliferative based and inflammation driven disease.

Drug discovery and development is a highly complex and costly endeavor, typically requiring over a decade and substantial financial investment to bring a new drug to market. Traditional computer-aided drug design (CADD) has made significant progress in accelerating this process, but the development of quantum computing offers potential due to its unique capabilities. This paper discusses the integration of quantum computing into drug discovery and development, focusing on how quantum technologies might accelerate and enhance various stages of the drug development cycle. Specifically, we explore the application of quantum computing in addressing challenges related to drug discovery, such as molecular simulation and the prediction of drug-target interactions, as well as the optimization of clinical trial outcomes. By leveraging the inherent capabilities of quantum computing, we might be able to reduce the time and cost associated with bringing new drugs to market, ultimately benefiting public health.

Recent advancements in nanotechnology have led to the development of multifunctional iron oxide nanoparticles, presenting new opportunities in cancer therapy. This study aimed to synthesize and evaluate citric acid-coated/ folic acid conjugated nanoparticles loaded with doxorubi-cin and investigate their efficacy in experimental tumor models. For synthesis, controlled co-precipitation method was employed to produce highly dispersive, multifunctional nanofluids with a narrow size distribution of iron oxide nanoparticles. Nanoparticles were characterized using Dynamic Light Scattering (DLS) and Electrophoretic Light Scattering (ELS) for size distribution and zeta potential, X-ray Diffraction (XRD) and Transmission Electron Microscopy (TEM) for structure and morphology, Vibrating Sample Magnetometry (VSM) for magnetic properties, and UV-Visible (UV-Vis) and Fourier-Transform Infra-red (FTIR) spectroscopy for modification confirmation. In vitro experiments employed RM1 (prostate cancer) and MEC1 (Chronic lymphocytic leukemia) cell lines to assess cytotoxicity and drug delivery efficiency. Fluorescence microscopy confirmed the intracellular delivery of doxorubicin by these nanoparticles, highlighting their potential for targeted therapy. As a result, nanoparticles conjugated with folic acid showed reduced efficacy over time. This study underscores the critical role of nanoparticle modifications in optimizing therapeutic outcomes. Future research should focus on further refining nanoparticle formulations and long-term effects in vivo, for development of effective and safe agents for targeted cancer treatment.

Introduction: Peripheral neuropathies are very common and occur due to multiple causes including diabetes, tuberculosis, vasculitis, thyroid disorders, immune mediated diseases, vitamin B12 deficiency and drugs. Drug induced peripheral neuropathy (DIPN) is potentially irreversible, resulting in sensory deficits and paraesthesia. DIPN due to anti-tubercular drugs is common and can be implicated on linezolid, cycloserine and isoniazid.Case: 40-year-old female, diabetic with MDR-TB presented with severe, sharp, burning pain in her lower limbs. The patient was on all longer acting ATT drug regimen and was suspected with drug induced peripheral neuropathy. Conclusion: Linezolid, is used in treatment of tuberculosis and one of the major side effects includes peripheral neuropathy which is usually quite severe, presenting predominantly with sensory symptoms. Cessation of linezolid and neuropathic pain medications reduced the pain of patient from VCPS 8-10 to 1-2. Treatment of DIPN can be challenging as adverse drug reactions while treating tuberculosis should be kept in mind. It also warrants earliest treatment by identification of the drug in disguise and timely discontinuation of the drug.

The rapid evolution of drug resistance is one of the greatest health issues of the 21st century. There is an alarming situation to find new therapeutic strategies or candidate drugs to tackle ongoing multi-drug resistance development. The marine environment is one of the prime natural ecosystems on Earth, the majority of which is still unexplored, especially when it comes to the microbes. A wide variety of bioactive compounds have been obtained from a varied range of marine organisms, however, marine bacteria-produced bacteriocins are still undermined. Owing to the distinct environmental stresses that marine bacterial communities encounter, their bioactive compounds frequently undergo distinct adaptations that confer on them a variety of shapes and functions, setting them apart from their terrestrial counterparts. The ribosomally-synthesized and posttranslationally modified peptides (RiPPs), bacteriocins are of special interest because of their variety in structure and diverse potential biological activities. Additionally, the gut microbiome of marine creatures are largely unexplored source of new bacteriocins with promising activities. There is a huge possibility of novel bacteriocins from marine bacterial communities that might come out as efficient candidates to fight against antibiotic resistance, especially in light of the growing pressure from antibiotic-resistant diseases and industrial desire for innovative treatments. The present review summarizes known bacteriocins from marine bacteria, evolutionary aspects, challenges, and huge possibilities of unexplored bacteriocins from marine bacterial communities.

The medical research field has been tremendously galvanized to improve the prediction of therapy efficacy by the revolution in artificial intelligence (AI). An earnest desire to find better ways to predict the effectiveness of therapy with the use of AI has propelled the evolution of new models in which it can become more applicable in clinical settings such as breast cancer detection. However, in some instances, the U.S. Food and Drug Administration was obliged to back some previously approved inaccurate models for AI-based prognostic models because they eventually produce inaccurate prognoses for specific patients who might be at risk of heart failure. In light of instances in which the medical research community has often evolved some unrealistic expectations regarding the advances in AI and its potential use for medical purposes, implementing standard procedures for AI-based cancer models is critical. Specifically, models would have to meet some general parameters for standardization, transparency of their logistic modules, and avoidance of algorithm biases. In this review, we summarize the current knowledge about AI-based prognostic methods and describe how they may be used in the future for predicting antibody-drug conjugate efficacy in cancer patients. We also summarize findings of recent late-phase clinical trials using these conjugates for cancer therapy.

Objectives: To analyze the clinical characteristics and factors associated with adverse drug reactions (ADR) in liver cancer patients receiving oxaliplatin‐based hepatic arterial infusion chemotherapy (HAIC). Methods: A retrospective analysis was performed on the clinical data of 137 patients with liver cancer who received oxaliplatin‐based HAIC. Changes in baseline characteristics, inflammatory factors, and other laboratory indicators in the no‐ADR and ADR groups were analyzed. Results: The incidence of serious ADR (CTCAE ≥ 3) was 21.9% (30/137). There was no significant difference in the cumulative dose of oxaliplatin between the two groups [157.3 (80.3, 322.4) vs. 206.6 (139.1, 324.2), P=0.161]. The increase in NEUT and IL‐6 was greater in the group treated with ADR than in the group not treated with ADR. Changes in NEUT [4.1 (1.5, 6.2) vs. 2.5 (0.5, 4.9), P=0.045] and changes in NEUTIL‐6 [4.2 (‐0.2, 22.9) vs. 0.8 (‐3.9, 7.7), P=0.026]. TBIL, ALT, AST, ALP, WBC, NEUT, PCT, CRP, TNF, IL‐2R, IL‐6, and IL‐10 were significantly higher after treatment than before in the ADR group (P < 0.05). In contrast, ALB and AFP were decreased. Conclusions: The severe ADR (CTCAE ≥ 3) associated with oxaliplatin‐based HAIC may be closely related to increased inflammatory factors such as NEUT and IL‐6. We should be vigilant for allergic reactions to oxaliplatin and increase monitoring during treatment

Marijuana is the most used illicit drug among youths in the United States. The objectives of the study were to identify the association between marijuana use and other risk behaviors including suicidality among high school students. The 2021 Mississippi Youth Risk Behavior Survey data sets were combined for this study. Crude odds ratio (OR) and adjusted odds ratio (AOR) with a 95% confidence interval were generated using the survey packages in R to account for weights and the complex sampling design of YRBS data. Tobacco products and alcohol use were significantly associated with marijuana use. Students who responded “Yes” to questions “currently used an electronic vapor product?”, “currently smoked cigarettes or cigars?” or “currently drank alcohol?” were more likely to use marijuana compared to students who responded “No”, after adjusting for other risk factors. Marijuana use is also significantly associated with students who had sex, compared to those who never had sex. The adjusted odds ratio is nearly doubled in those who had sex with the same sex or both sexes, compared to those who had heterosexual sex only. After adjusting for other health risk factors, the association between current marijuana use and attempted suicide was not statistically significant. The impact of students’ not sleeping in their parent's or guardian's home on current marijuana use was not significant after adjusting for other risk factors. Marijuana use is evenly burdened between males and females and between all race categories among Mississippi high school students. The identified associations seem to indicate that electronic vapor, tobacco products, and alcohol use could be the forerunners for drug use and should be treated accordingly in drug use prevention programs.

The incidence of infections due to carbapenemase-producing Enterobacteriaceae (CPE) is rising worldwide. We present the case of a 48-year-old female patient, diabetic, with previous episodes of urinary tract infections that was admitted due to pyelonephritis, later identified to be caused by KPC and ESBL-producing Klebsiella pneumoniae. Both the patient and her family had no strong epidemiological link with the healthcare system, and for this reason, this case stands out in regional literature since similar reports are scarce and therefore constitutes a reason for alert in health institutions. Further studies are needed in order to ascertain the real incidence of these infections in community settings in Latin America and the Caribbean.

Background : Drug treatments for gait disorders in post-stroke patients aim to reduce muscular hyperactivity. Analysis of muscle activity is essential to help clinicians understand these disorders. The aim of this study was to quantify changes in muscle synergies before (PRE) and after (POST) rectus femoris nerve block. Methods : Gait analysis of 8 post-stroke patients before and immediately after nerve block. Muscle synergies were quantified from electromyographic signals. We have selected: the account for variance indicating the robustness of the synergies, the recruitment selectivity index indicating the degree of multiplexing of the synergies, and the recruitment consistency index indicating the variability of the synergies. Results : A decrease in VAF is observed, suggesting a reduction in gait pattern robustness. We also note that spatial and temporal primitives are slightly different (IRC, IRS) in PRE vs. POST, and that their activation is more nested in POST than in PRE. Conclusions : The motor nerve block has not created new muscle synergies of the paretic limb during gait, but indicates that there is flexibility in motor organization. This method of quanti-fication may enable clinicians to assess the motor adaptation potential of their post-stroke patient.

Microneedle technology is a novel platform technology that revolutionizes ocular drug delivery and addresses critical challenges in the treatment of ocular diseases. Routine treatment methods, such as eye drops and intravitreal injections, suffer from low bioavailability and poor patient compliance. So, novel advanced platform technologies are required to overcome these challenges. Microneedle is a minimally invasive and promising alternative technique that helps precisely control drug delivery to targeted tissues and organs. This review investigates the potential impact of microneedle technology for eye care, underscoring recent advancements, underlying mechanisms, and emerging preclinical and clinical uses. Different types of microneedles, including solid, coated, dissolvable, and hollow, have demonstrated their potential and capability to bypass several barriers in the cornea and sclera. This ensures effective drug penetration and delivery. The current innovations in material science and fabrication methods have enhanced the safety and efficacy of microneedles, reducing discomfort and the chances of infections. These microneedle technologies offer sustained and controlled drug delivery, which could improve therapeutic outcomes for various disease conditions like age-related macular degeneration, glaucoma, diabetic neuropathy, etc. In the current review, recent preclinical and clinical studies emphasize microneedle-based ocular drug delivery's feasibility and potential benefits. These include improved pharmacokinetics, reduced dosing frequency, enhanced patient adherence, and, most importantly, microneedles offer versatile platforms for delivering a wide range of small and large molecules and gene therapies. Despite the exciting progress, obstacles such as regulatory barriers, scalability, and long-term biocompatibility persist. It will be essential to tackle these challenges through interdisciplinary research and partnerships to integrate microneedle technology into standard clinical use effectively. Ultimately, microneedle drug delivery offers a revolutionary method that has the potential to significantly enhance the treatment and results of ocular diseases, marking the dawn of a new era in eye care.

Numerous study reports on chitosan hydrogels in different forms such as films, porous structures, nanoparticles, and microspheres for biomedical applications, however, this study concentrates on their modifications with different crosslinking agents and observing their effects on drug loading and releasing capacities. Linear chitosan along with crosslinked by two major cross-linkers, i.e., genipin and disulfide have been used to formulate three different hydrogel systems. The cross-linking process is heavily impacted by the temperature and the pH conditions. Three different drugs, i.e., thymoquinone, gefitinib, and erlotinib are loaded in phosphate buffer solutions and infused with three different hydrogel systems, thus, a total of nine combinations are studied and analyzed for drug loading and releasing capabilities with Ultraviolet–visible (UV-Vis) spectroscopy. This study finds thymoquinone shows the lowest loading efficacy compared to two other drugs in all three systems. Gefitinib shows stable loading and releasing regardless of crosslinking systems and genipin crosslinked system shows stable loading and releasing with all three drug molecules. These experimental results agree well with the findings of our previously published results conducted with molecular dynamics simulations.

Biomaterials are the basis for the development of medicine because they allow safe contact with a living organism. The aim of this work was to produce innovative oxide layers with a porous microstructure on the surface of commercially pure titanium Grade 4 (CpTi G4), and to characterize their properties as drug carriers. Anodization of the CpTi G4 subjected to mechanical grinding and electrochemical polishing was carried out in a solution of 1M ethylene glycol with the addition of 40 g of ammonium fluoride at a voltage of 20 V for 2, 18, 24 and 48 hours at room temperature. It was found that the longer anodization time, the greater the number of pores formed on the CpTi G4 surface as revealed by FE-SEM method, and the greater the surface roughness determined in profilometric tests. As the anodizing time increases, the amount of the drug in the form of gentamicin sulfate incorporated into the resulting pores decreases. The most favorable drug release kinetics profile determined by UV-VIS absorption spectroscopy was found for the CpTi G4 anodized for 2 h making them the best choice when it comes to the drug carrier allowing full use of the therapeutic dose of the drug.

Drug-induced liver disease represents one of the main problems in the therapeutic field. As with most pathologies, also in this case various risk factors can be recognised, such as age, sex, but also the gut microbiota. Therefore all drugs on the market can, in fact, cause hepatotoxicity of varying degrees. Drugs used in the treatment of IBD can also cause these adverse effects and even lead to DILI. In this review, the various classes of drugs used in the treatment of IBD were taken into consideration and the various adverse effects on the liver were illustrated. In particular, a major role has emerged regarding hepatotoxicity of immunosuppressants. Biological drugs, however, seem to be responsible for these complications to a much lesser extent.

Post-operative chemotherapy is still required for the treatment of glioblastoma (GBM), and nanocarrier-based drug delivery has been identified as one of the most effective methods. However, the blood-brain barrier (BBB) and non-specific delivery to non-tumor tissues can significantly limit drug accumulation in tumor tissues and cause damage to nearby normal tissues. This study describes a targeted cancer therapy approach that uses AS1411 aptamer-conjugated nanospheres, 100-300 nm in size, loaded with doxorubicin (Dox) to selectively identify tumor cells overexpressing nucleolin (NCL) proteins. The study demonstrates that the active target model, which employs aptamer-mediated drug delivery, is more effective than nonspecific enhanced permeability and maintenance (EPR)-mediated delivery and passive drug delivery in improving drug penetration and maintenance in tumor cells. Additionally, the study shows the potential for anticancer effects through 3D spheroidal and in vivo GBM xenograft models. The DNA-protein hybrid nanospheres utilized in this study offer numerous benefits, such as efficient synthesis, structural stability, high drug loading, dye labelling, biocompatibility, and biodegradability. When combined with nanospheres, the 1411 aptamer has been shown to be an effective drug delivery carrier for precisely targeting tumors. This combination has the potential to produce anti-tumor effects in active targeted therapy of GBM.

This article delves into the intersection of generative AI and digital twins within drug discovery, exploring their synergistic potential to revolutionize pharmaceutical research and development. Through various instances and examples, we illuminate how generative AI algorithms, capable of simulating vast chemical spaces and predicting molecular properties, are increasingly integrated with digital twins of biological systems to expedite drug discovery. By harnessing the power of computational models and machine learning, researchers can design novel compounds tailored to specific targets, optimize drug candidates, and simulate their behavior within virtual biological environments. This paradigm shift offers unprecedented opportunities for accelerating drug development, reducing costs, and, ultimately, improving patient outcomes. As we navigate this rapidly evolving landscape, collaboration between interdisciplinary teams and continued innovation will be paramount in realizing the promise of generative AI and digital twins in advancing drug discovery.

Glioblastoma, a deadly brain tumor, shows limited response to standard therapies like te-mozolomide (TMZ). Recent findings from the REGOMA trial underscore a significant survival improvement offered by regorafenib (REGO) in recurrent glioblastoma. Our study aimed to propose a 3D ex vivo drug response precision medicine approach to investigate recurrent glio-blastoma sensitivity to REGO and elucidate the underlying molecular mechanisms involved in tumor resistance or responsiveness to treatment. 3D glioblastoma organoids (GB-EXPs) obtained from 18 patients’ resected recurrent glioblastoma tumors were treated with TMZ and REGO. Drug responses were evaluated using NAD(P)H FLIM, stratifying tumors as responders (Resp) or non-responders (NR). Whole-exome sequencing was performed on 16 tissue samples, and whole-transcriptome analysis on 13 GB-EXPs treated and untreated. We found 35% (n=9) and 77% (n=20) of tumors responded to TMZ and REGO, respectively, with no instances of TMZ-Resp be-ing REGO-NR. Exome analysis revealed a unique mutational profile in REGO-Resp tumors compared to NR tumors. Transcriptome analysis identified distinct expression patterns in Resp and NR tumors, impacting Rho GTPase and NOTCH signaling, known to be involved in drug response. In conclusion, recurrent glioblastoma tumors were more responsive to REGO com-pared to TMZ treatment. Importantly, our approach enables a comprehensive longitudinal ex-ploration of the molecular changes induced by treatment, unveiling promising biomarkers in-dicative of drug response.

The persistent threat of cancer remains a significant hurdle for global health, prompting the exploration of innovative approaches in the quest for successful therapeutic interventions. Cyclin-dependent kinase 9 (CDK9), a central player in transcription regulation and cell cycle progression, has emerged as a promising target to combat cancer. Its pivotal role in oncogenic pathways and the pressing need for novel cancer treatments has propelled CDK9 into the spotlight of drug discovery efforts. This article presents a comprehensive study that connects a multidisciplinary approach, combining computational methodologies, experimental validation, and the transformative PROTAC (Proteolysis-Targeting Chimera) technology. By uniting these diverse techniques, we aim to identify, characterize, and optimize a new class of degraders targeting CDK9. We explore these compounds for kinase inhibitory properties and potential to induce targeted protein degradation, offering a novel and potentially more sustainable approach to cancer therapy. This cohesive strategy expresses the interface between computational predictions and experimental insights, with the ultimate goal of advancing the development of effective anticancer therapeutics targeting CDK9.

Background: Chronic Myeloid Leukemia (CML) is initiated in bone marrow due to chromosomal translocation t(22;9) leading to fusion oncogene BCR-ABL. Targeting BCR-ABL by tyrosine kinase inhibitors (TKI) have changed fatal CML into an almost curable disease. Despite that, TKIs lose their effectiveness due to disease progression. Unfortunately, mechanism of CML progression is poorly understood and common biomarkers for CML progression are unavailable. This study was conducted to find out novel biomarkers of CML progression by employing whole exome sequencing (WES).Materials and Methods: WES of accelerated phase (AP-) and blast crisis (BC-) CML patients was carried out, with chronic phase CML (CP-CML) patients as control. After DNA library preparation and exome enrichment, clustering and sequencing was carried out using Illumina platforms. Statistical analysis was carried out using [SAS/STAT] software version 9.4 and R package employed to find mutations shared exclusively by all AP-/BC-CML. Confirmation of mutations was carried out using Sanger sequencing and protein structure modelling using I-Tasser followed by mutant generation and visualization using PyMOL. Results: Three novel genes (ANKRD36, ANKRD36B and PRSS3) were mutated exclusively in all AP-/BC-CML patients. Only ANKRD36 gene mutations (c.1183_1184 delGC and c.1187_1185 dupTT) were confirmed by Sanger sequencing. Protein modelling studies showed that mutations induce structural changes in ANKRD36 protein. Conclusions: Our studies show that ANKRD36 is a potential common biomarker and drug target of early CML progression. ANKRD36 is yet uncharacterized in human. It has the highest expression in bone marrow, specifically myeloid cells. We recommend carrying out further studies to explore the role of ANKRD36 in biology and progression of CML.

Tongue mobility is an obstructive sleep apnoea (OSA) marker and myofunctional therapy (MFT) target. For this reason, all patients with sleep-disordered breathing should require a combined functional assessment from an ear, nose, and throat (ENT) specialist and a phonoaudiologist to confirm or rule out the presence of tongue-tie. To our knowledge, this is the first case of a 13-year-old girl diagnosed with severe OSA and a significant decrease of 94% in her apnoea index (AI), requiring frenotomy with immediate postoperative change in the tongue position. A drug-induced sleep en-doscopy (DISE) was performed before and immediately post-frenotomy, and the anatomical changes provoked by this surgery during sleep were confirmed for the first time.

In recent years, the emergence of cancer drug resistance is one of the crucial tumor hallmarks which is supported by the level of genetic heterogeneity and complexities at cellular levels. Oxidative stress, immune evasion, metabolic reprogramming, overexpression of ABC transporters and stemness are among the several key contributing molecular and cellular response mechanisms. Topo-active drugs, e.g., doxorubicin and topotecan, are clinically active and are utilized extensively against a wide variety of human tumors and often results in the development of resistance and failure to therapy. Thus, there is an urgent need for an incremental and comprehensive understanding of mechanisms of cancer drug resistance specifically in the context of topo-active drugs. This review delves into the intricate mechanistic aspects of these intracellular and extracellular topo-active drug resistance mechanisms and explores use of potential combinatorial approaches by utilizing various topo-active drugs and inhibitors of pathways involved in drug resistance. We believe that this review will help guide basic scientists, pre-clinicians, clinicians, and policymakers toward holistic and interdisciplinary strategies that transcend resistance, renewing optimism in the ongoing battle against cancer.

Breast cancer is a serious disease and the second leading cause of cancer-related death among women in the U.S. New treatments for this aggressive disease are urgently needed. Repurposing FDA-approved drugs for cancer treatment is an alternative that saves time and lowers the costs needed for drug development. In this study, we investigated the effects of proguanil, an anti-malarial drug, in breast cancer cells. Proguanil exhibited a significant cytotoxic effect on breast cancer cell lines including patient derived cell lines. Proguanil caused apoptosis through increased production of ROS and consequent decrease of mitochondrial membrane potential, mitochondrial respiration, and ATP production rates. ROS generation by proguanil was up to 3-fold higher when compared to the control. Proguanil treatment increased the expression of Bax, p-H2AX, cleaved-caspase 9, cleaved PARP, and down-regulated bcl-2 and survivin in breast cancer cell lines. The enlargement of 4T1 breast tumors in female Balb/c mice was suppressed by 55% through daily oral administration of 20mg/kg of proguanil. Western blot analyses of proguanil- treated tumors showed increased levels of p-H2AX, Bax, c-PARP, and c-caspase3 compared to control. Proguanil proved to be an efficient in vitro and in-vivo inhibitor of breast cancer cells, hence should be considered further for clinical investigation against breast cancer.

Classical Hodgkin lymphoma (cHL) is a highly curable disease (70-80%), even though long-term toxicities, drug resistance, and predicting clinical responses to therapy are major challenges in cHL treatment. To solve these problems, we characterized two cHL cell lines with acquired resistance to doxorubicin, KM-H2dx and HDLM-2dx (HRSdx), generated from KM-H2 and HDLM-2 cells, respectively. HRSdx cells developed cross-resistance to vinblastine, bendamustin, cisplatin, dacarbazine, gem-citabine, brentuximab vedotin (BV), and γ-radiation. Both HDLM-2 and HDLM-2dx cells had an intrinsic resistance to BV but not to the drug MMAE. HDLM-2dx acquired cross-resistance to caelyx. HRSdx cells had in common: decreased CD71, CD80, CD54, cyt-ROS, HLA-DR, DDR1, CD44; increased Bcl-2, CD58, COX2, CD26, CCR5, invasive capability; increased CCL5, TARC, PGE2, TGF-β, and capability to hijack monocytes. In HRSdx cells, less sensitive to DNA damage and oxidative stress, the efflux drug transporters MDR1 and MRP1 were not up-regulated, and doxorubicin accumulated in cytoplasm rather than in nucleus. Both autophagy inhibitor chloroquine and extracellular vesicles (EVs) release inhibitor GW4869 enhanced doxorubicin activity and counteracted doxorubicin resistance. In conclusion, this study identifies common modulated antigens in HRSdx cells, the associated cross-resistance patterns, and new potential therapeutic options to enhance doxorubicin activity and overcome resistance.

Biofilm-associated proteins (BAPs) are important in the development and resilience of biofilms, which are intricate populations of microbes protected by extracellular matrix. All members of the BAP family are known to possess common characteristics such as high molecular weight and a signal sequence for extracellular secretion. It has been shown that BAPs are directly linked to the pathogenicity of many bacteria. This mini review highlights several potential strategies to target BAPs for drug development.

Idiosyncratic drug induced liver injury (DILI) is an unpredictable reaction of exposed individual on a certain drug, and the drug-induced autoimmune hepatitis (DIAIH) presents a DILI phenotype that mimics idiopathic autoimmune hepatitis (AIH) when considering the clinical, biochemical, serological and histological parameters. We present a case of a 48-year-old male that was hospitalized due to severe hepatocellular liver injury two months after the self-treatment with the muscle-building dietary supplement based on arginine-alpha-ketoglutarate, L-citrulline, L tyrosine, creatine malate and beet extract. His immunology panel was positive with increased IgG levels, and the radiologic methods showed no signs of chronic liver disease. He underwent corticosteroid treatment with adequate response. After the therapy withdrawal, a clinical relapse occurred. Seven months after the initial presentation liver MR suggested the initial cirrhotic changes of the right liver lobe. Liver biopsy revealed abundant lymphoplasmacytic infiltrate with piecemeal necrosis and grade 2 fibrosis. He responded well on the corticosteroid treatment again, and was further treated with low dose prednisone without additional relapses. Several years later, further management confirmed presence of liver cirrhosis with no histological or biochemical signs of the disease activity. DIAIH is a DILI phenotype difficult to distinguish from idiopathic AIH despite a wide armamentarium of diagnostic methods. Regular patient monitoring and clinical open-mindedness with the adjustment of therapeutic approaches according to the disease course are more important than strict labelling of the disease.

Diabetic kidney disease (DKD) is one of the leading causes of end-stage renal disease worldwide and significantly increases the risk of premature death due to cardiovascular diseases. Elevated urinary albumin levels are an important clinical feature of DKD. Effective control of albuminuria not only delays glomerular filtration rate (GFR) decline but also markedly reduces cardiovascular disease risk and all-cause mortality. New drugs for treating DKD proteinuria, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), mineralocorticoid receptor antagonists (MRAs), and endothelin receptor antagonists (REAs), have shown significant efficacy. Auxiliary treatment with proprietary Chinese medicine has also yielded promising results; however, it also faces a broader scope for development. The mechanisms by which these drugs treat albuminuria in patients with DKD should be described more thoroughly. The positive effects of combination therapy with two or more drugs in reducing albuminuria and protecting the kidneys warrant further investigation. Therefore, this review explores the pathophysiological mechanism of albuminuria in patients with DKD, the value of clinical diagnosis and prognosis, new progress and mechanisms of treatment, and multidrug therapy in patients who have type 2 diabetic kidney disease (T2DKD), providing a new perspective on the clinical diagnosis and treatment of DKD.

Infectious illnesses have always posed a threat to human health, with tuberculosis (TB) being a major concern. The use of various medications and antibiotics in the fight against such illnesses has led to the emergence of drug-resistant infectious diseases, which have become increasingly dif-ficult to manage as medical and scientific research has advanced. Inadequate medical infrastruc-ture, incorrect treatment practices that exacerbate resistance patterns, and transmission within communities and healthcare facilities are the main factors contributing to the spread of drug-resistant TB. Though treating individuals with multiple drug resistance (MDR) and extreme drug resistance (XDR) strains is challenging, early identification of resistance and the imple-mentation of a well-designed treatment regimen can result in a cure. Community-based inter-ventions that address socioeconomic barriers to adherence can also enhance treatment outcomes. While there have been few studies and proposed conceptual models on how to manage and prevent various drug-resistant TB mutations and lineages, a model aimed at limiting and controlling such mutations has been developed. This paradigm seeks to bridge the gap by facilitating the exchange of knowledge among healthcare professionals (HCP) in healthcare facilities (HCF), diagnostic laboratories (DL), and research institutes (RI), particularly for underprivileged communities in the Eastern Cape. The model guide will also monitor and evaluate TB management plans

Aim was to develop a population pharmacokinetic model for methotrexate (MTX) during high-dose treatment (HDMTX) in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin’s lymphoma (NHL) and to describe the sources of variability. The study included 50 patients (1-18 years) who received 3 or 5 g/m2 of HDMTX. Nonlinear mixed effects modeling approach was applied for data analysis. Parameter estimation was performed by FOCEI, whereas stepwise covariate modeling was used to assess variability factors. The final two-compartment model incorporates the effect of body weight using allometric scaling and the influence of hemoglobin and serum creatinine on MTX clearance (CL). Population pharmacokinetic values for a typical 70 kg subject were: 11 L/h for clearance (CL), 46.5 L and 16.4 L for volume of central (V1) and peripheral compartment (V2), respectively, and 0.168 L/h for intercompartmental clearance (Q). According to the final model, MTX CL decreases with increasing serum creatinine, whereas a positive effect was captured for hemoglobin. A difference of almost 30% in MTX CL was observed among patients’ hemoglobin values reported in the study. In addition to renal function and body weight, it describes the influence of hemoglobin on CL, allowing better understanding of its contribution to HDMTX disposition.

Buckground: Although ceftazidime/avibactam (CAZ/AVI) has become important option for treating adults and children, no recommendations exist for neonates. We report a neonatal sepsis case due to CAZ/AVI-resistant KPC-2 producing-Klebsiella pneumoniae carrying blaVEB-25 and the use of a customized active surveillance program in conjunction to infection control measures. Methods: The index case was an extremely premature neonate hospitalized for 110 days that had been previously treated with multiple antibiotics. Customized molecular surveillance was implemented at hospital level and enhanced infection control measures were taken for early recognition and prevention of outbreak. Detection and identification of blaVEB-25 was performed by next-generation sequencing. Results: That was the first case of a bloodstream infection caused by KPC producing K. pneumoniae that was resistant to CAZ/AVI without the presence of a metalo-β-lactamase in the multiplex PCR platform in a neonate. All 36 additional patients tested (12 in the same NICU and 24 from other hospital departments) carried wild-type blaVEB-1 but they did not harbor blaVEB-25. Conclusion: The emergence of VEB-25 is signal for horizontal transfer of plasmids at hospital facilities and it is of greatest concern for maintaining a sharp vigilance for surveillance of novel resistance mechanisms. Molecular diagnostics can guide appropriate antimicrobial therapy and early implementation of infection control measures against antimicrobial resistance.

The current study aims to first, isolate H. pylori in cultures from gastric biopsy samples and test their susceptibility. Secondly, we aim to assess the efficacy of the standard triple therapy from patients coming of the western central region of Colombia. Patients with H. pylori positive re-ceived standard triple therapy with PPI [40 mg b.i.d.], clarithromycin [500 mg b.i.d.], amoxicillin [1g b.i.d.] for 14 days. Thereafter, antibiotic susceptibility of the isolates was assessed by E-Test. From 94 patients enrolled, 67 were positive for H. pylori by histology or culture. Resistance to metronidazole, levofloxacin, rifampicin, clarithromycin and amoxicillin was 81, 26.2, 23.9, 19 and 9.5%, respectively. No resistance was found for tetracycline. 54 patients received standard triple therapy, 48 attended follow-ups testing and of them, 30 had resistance test reports. Overall eradication rate was 81.2%, 4 patients underwent second-line management and only one patient remained H. pylori positive by urea breath test during the follow-up [six weeks]. Eradication was significantly higher in patients with clarithromycin susceptible than in resistant strains [95.6% vs. 42.8% p= 0.001]. The updated percentages of resistance to clarithromycin in this geographical area have increased, so this value must be considered when choosing the treatment regimen.

Drug delivery systems consist of cyclodextrins (CyDs) have kept constant attention for good compatibility, negligible toxicity, and improved pharmacokinetics of drugs. The unique hollow structure has endowed a lot of functions, such as inclusion of guest molecules, functional modification of active hydroxyl groups, and noncovalent interactions. Besides, the polyhydroxy structure has further extended the functions of CyDs by inter/intramolecular interactions and chemical modification. Furthermore, the versatile functions of the complex contribute to physicochemical characteristics alteration of the drugs, therapeutic talent, stimulus-responsive switch, self-assemble capability, and fiber formation. This review attempts to list the recent progress of CyDs and discuss their roles in the drug delivery system. Future perspectives of the construction of CyD-based drug delivery systems are also discussed at the end of this review, which may be the possible directions for the construction of more rational and cost-effective delivery vehicles.

The repurposing of licenced drugs for use against COVID-19 is one of the most rapid ways to develop new and alternative therapeutic options to manage the ongoing pandemic. Given the approximately 8,000 licenced compounds available from Compounds Australia that can be screened, this paper demonstrates the utility of commercially-available ex vivo/3D airway and alveolar tissue models. These models are a closer representation of in vivo studies compared to in vitro models, but retain the benefits of rapid in vitro screening for drug efficacy. We demonstrate that several existing drugs appear to show anti-SARS-CoV-2 activity against both Delta and Omicron Variants of Concern in the airway model. In particular, fluvoxamine, as well as aprepitant, everolimus, and sirolimus have virus reduction efficacy comparable to the current standard of care (remdesivir, molnupiravir, nirmatrelvir). Whilst these results are encouraging, further testing and efficacy studies are required before clinical use can be considered.

Hydrogels can provide instant relief to pain and facilitate the fast recovery of wounds. Currently the incorporation of medicinal herbs/plants in polymer matrix is being investigated due to their anti-bacterial and wound healing properties. Herein, we investigated the novel combination of chitosan (CS), chondroitin sulfate (CHI) and garlic (Gar) to synthesize hydrogels through freeze gelation process for faster wound healing and resistance to microbial growth at the wound surface. The synthesized hydrogels were characterized via Fourier transform infrared spectroscopy (FTIR), which confirmed the presence of relevant functional groups. The scanning electron microscopy (SEM) images exhibited the porous structure of the hydrogels, which is useful for the sustained release of Gar from the hydrogels. The synthesized hydrogels showed significant inhibition zones against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Furthermore, cell culture studies confirmed the cyto-compatibility of the synthesized hydrogels. Thus, the novel hydrogels presented in this study can offer antibacterial effect during wound healing and promote tissue regeneration.

Targeted delivery of drugs or other therapeutic agents through internal or external triggers has been used to control and accelerate the release from liposomal carriers in a number of studies, but relatively few utilize energy of therapeutic X-rays as a trigger. We have synthesized liposomes that are triggered by ionizing radiation (RTLs) to release their therapeutic payload. These liposomes are composed of natural egg PE, DSPC, cholesterol, and DSPE-PEG-2000, and the mean size of the RTL was in the range of 114 to 133 nm, as measured by NTA. The trigger mechanism is the organic halogen, chloral hydrate, which is known to generate free protons upon exposure to ionizing radiation. Once protons are liberated, a drop in internal pH of the liposome promotes destabilization of the lipid bilayer and escape of the liposomal contents. In proof of principle studies, we assessed RTL radiation-release of fluorescent tracers upon exposure to a low pH extracellular environment or exposure to X-ray irradiation. Biodistribution imaging before and after irradiation demonstrated a preferential uptake and release of the liposomes and their cargo at the site of local tumor irradiation. Finally, a potent metabolite of the commonly used chemotherapy irinotecan, SN-38, was loaded into RTL along with near infrared (NIR) fluorescent dyes for imaging studies and measuring tumor cell cytotoxicity alone or combined with radiation exposure, in vitro and in vivo. Fully loaded RTLs were found to increase tumor cell killing with radiation in vitro and enhance tumor growth delay in vivo after three i.v. injections combined with three, 5 Gy local tumor radiation exposures compared to either treatment modality alone.

The prediction of drug-target interactions plays a fundamental role in facilitating drug discovery, where the goal is to find prospective drug candidates. With the increase in the number of drug-protein interactions, machine learning techniques, especially deep learning methods, have become applicable for drug-target interaction discovery because they significantly reduce the required experimental workload. In this paper, we present a spontaneous formulation of the drug-target interaction prediction problem as an instance of multi-instance learning. We address the problem in three stages, first organizing given drug and target sequences into instances via a private-public mechanism, then identifying the predicted scores of all instances in the same bag, and finally combining all the predicted scores as the output prediction. A comprehensive evaluation demonstrates that the proposed method outperforms other state-of-the-art methods on three benchmark datasets.

Background: A novel virulent coronavirus is what causes Novel Corona-virus Disease 2019 (nCOVID 19). It results in severe respiratory distress syndrome and potentially fatal infectious pneumonia. On March 12, 2020, the World Health Organization first labeled it a pandemic, which was then followed on the same day by a community health emergency of global concern. Vaccines against this deadly virus are now being created. Many drugs with different uses have been repurposed and tested for the prevention and treatment of the infection. Objective: The purpose of this review is to provide an in-depth analysis of data on possible pharmacological targets and available coronavirus treatments. Methods: Following the review protocol, a literature search was conducted. Results: Chloroquine phosphate and hydroxychloroquine, Remdesivir, and Lopinavir-Ritonavir in combination with or without interferon and convalescent plasma therapy are the main treatment candidates, according to the World Health Organization. This review article has elaborated on the current evidence of prospective pharmacological targets and related ongoing research, including inflammatory chemicals, bioactive peptides, beta cells, platelets, and the Angiotensin I Converting Enzyme 2 Receptor. This information was gathered from published journals. In addition, stories of medications and biological products like interferons and vaccinations that are utilized or could be utilized have been provided. Conclusion: There are a variety of pharmacological targets and therapeutic strategies that need more study.

Here we draw insights from the latest serendipitous findings made on the opposing roles of a validated drug-target protein Keap1. We weigh up how natural reactive electrophiles and electrophilic small-molecule drugs in clinical use directly impinge on seemingly conflicting, yet both Keap1-electrophile-modification-dependent, cell-survival- vs. cell-death-promoting behaviors. In the process, we convey how understanding reactive chemical-signal regulation at a single-protein-specific level is an enabling necessity in deconstructing otherwise intricate reactive-small-molecule-responsive cellular pathways. We hope this opinion piece further spurs the broader interests of basic and pharmaceutical research communities toward better understanding of molecular mechanisms underpinning reactive small-molecule-regulated signaling subsystems.

Cryptococcus neoformans causes meningoencephalitis in immunocompromised individuals, which is treated with Fluconazole (FLC) monotherapy when resources are limited. This can lead to azole resistance, which can be mediated by overexpression of ABC transporters, a class of efflux pumps. ABC pump-mediated efflux of FLC is also augmented in 10-generation old C. neoformans cells. Here, we describe a new ABC transporter Afr3 (CNAG_06909), which is overexpressed in C. neoformans cells of advanced generational age, that accumulate during chronic infection. The delta-afr3 mutant strain showed higher FLC susceptibility by FLC E-Test strip testing and also by a killing test that measured survival after 3 h FLC exposure. Furthermore, delta-afr3 cells exhibited lower Rhodamine 6G efflux compared to the H99 wild type cells. Afr3 was expressed in the Saccharomyces cerevisiae AD-delta strain, which lacks several drug transporters, thus reducing background transport. The AD-delta + Afr3 strain demonstrated a higher efflux with both Rhodamine 6G and Nile Red, even though the FLC MICs were not changed. Characterization of the delta-afr3 mutant revealed unattenuated growth but a prolongation (22%) of the replicative life span. In addition, delta-afr3 exhibited decreased resistance to macrophage killing and attenuated virulence in the Galleria mellonella infection model. In summary, our data indicate that a novel ABC pump Afr3p, which is upregulated in C. neoformans cells of advanced age may contribute to their enhanced FLC tolerance, by promoting drug efflux. Lastly, its role in macrophage resistance may also contribute to the selection of older C. neoformans cells during chronic infection.

The most effective method of treating allergic diseases, aimed not at relieving symptoms, but at eliminating the cause of the disease, is allergen-specific immunotherapy (AIT). To reduce the risk of side effects and improve the delivery of allergens to the mucosa, various delivery systems, such as liposomes, dendrimers, nanoparticles, etc., can be used. To date, there are data on the creation of delivery systems based on glycyrrhizic acid (GA) and its derivatives, but such a delivery system has not been used for allergen-specific therapy until now. At the same time, it is known that GA has an anti-inflammatory effect, shifts the balance towards Th1, and increases the number of Treg cells, which means that in the future it can enhance the anti-allergic effect of AIT and reduce the risk of unwanted side effects. Thus, the study of the immunomodulatory effect of supramolecular complexes (micelles) of GA with extracts of allergens seems to be very promising for the development of new drugs for AIT.

Metastasis is the leading cause of cancer death and can be realized through the phenomenon of tumor cell fusion. The fusion of tumor cells with other tumor or normal cells leads to the appearance of tumor hybrid cells (THCs) exhibiting novel properties such as increased proliferation and migration, drug resistance, decreased apoptosis rate and avoiding immune surveillance. Experimental studies showed the association of THCs with a high frequency of cancer metastasis; however, the underlying mechanisms remain unclear. Many other questions also remain to be answered: the role of genetic alterations in tumor cell fusion, the molecular landscape of cells after fusion, the lifetime and fate of different THCs, and the specific markers of THCs, and their correlation with various cancers and clinicopathological parameters. In this review, we discuss the factors and potential mechanisms involved in the occurrence of THCs, the types of THCs, and their role in cancer drug resistance and metastasis, as well as potential therapeutic approaches for the prevention and targeting of tumor cell fusion. In conclusion, we emphasize the current knowledge gaps in the biology of THCs that should be addressed to develop highly effective therapeutics and strategies for metastasis suppression.

Molecular Dynamics (MD) simulations model motion of molecules in atomistic detail and aid in drug design. While simulations on large systems may require several days to complete, analysis of terabytes of data generated in the process could also be time consuming. Recent studies captured exciting and dramatic drug-receptor interactions under cell-like complex conditions. Such advances make simulations of biomolecular interactions more realistic, insightful, and informative and have potential to make drug design more realistic. However, currently available resources and techniques do not provide, in reasonable time, a comprehensive understanding of events seen in simulations. We demonstrate that big data approach results in significant speedups, and provides rapid insights into simulations performed. Advancing this improvement, we propose a scalable, self-tuning, and responsive framework based on Cloud-infrastructure to accomplish the best possible MD studies with given priorities and within available resources.

The family environment has an important role in determining children’s personality and behavior. This study examined the impact of the family environment on alcohol and drug misuse among Indonesian students. Data were obtained from the National Illicit Drug Use Survey of students in Indonesia in 2016, conducted in 18 provinces. The subjects were 35,340 students from 1284 schools and universities with an age range of 12-25 years. The survey used the self-administered modified NODC Structured Illicit Drug questionnaire. The results show that 13.7% of students ever drank alcohol and 2.1% of students misused drugs within the previous year. Among students who drank alcohol, 11% also used drugs. In the latter group, they were likely to have been victims of verbal and physical violence by their parents and never discussed any problems with their parents. Living with a family with existing risky behavior (alcohol drinking and/or drug misuse) was the strongest risk factor of alcohol drinking (aOR: 4.78; 4.27-5.37) and drug misuse (aOR: 2.32; 1.79-3.01). These results indicate that the family environment affects these risky behaviors in this target population. Making adjustments through parental support, control, and parenting style, particularly in initiating parent–child communication, may have benefits in preventing alcohol drinking and drug use in this target population.

Individual response to drugs is highly variable and largely influenced by genetic variants and gene-expression profiles. Also, it has been shown that response to drugs is strongly sex-dependent, both in terms of efficacy and toxicity. To expand current knowledge on sex differences in the expression of genes relevant for drug response, we generated a catalogue of differentially expressed human transcripts encoded by 289 genes in 41 human tissues from 838 adult individuals of the Genotype-Tissue Expression project (GTEx, v8 release) and focused our analysis on relevant transcripts implicated in drug response. We have detected significant sex-differentiated expression of 99 transcripts encoded by 59 genes in the tissues most relevant for human pharmacology (Liver, Lung, Kidney, Small intestine terminal ileum, Skin not sun-exposed, and Whole Blood). Among them, as expected, we observed significant differences in the expression of transcripts encoded by the cytochromes in the liver, CYP2B6, CYP3A7, CYP3A5, and CYP1A1. Our systematic investigation on differences between male and female in the expression of drug response related genes, reinforce the need to overcome the sex bias of clinical trials.

The multidrug efflux transporter ABCB1 is clinically important for drug absorption and distribution and can be a determinant of chemotherapy failure. Recent structure data shows that three glutamines donate hydrogen bonds to co-ordinate taxol in the drug binding pocket. This is consistent with earlier drug structure-activity relationships that implicated the importance of hydrogen bonds in drug recognition by ABCB1. By replacing the glutamines with alanines we have tested whether any or all of Q347, Q725 and Q990 are important for the transport of three different drug classes. Flow cytometric transport assays show that Q347A and Q990A act synergistically to reduce transport of Calcein-AM, BODIPY-verapamil and OREGON GREEN-taxol bisacetate but the magnitude of the effect was dependent on the test drug and no combination of mutations completely abrogated function. Surprisingly, Q725A mutants generally improved transport of Calcein-AM and BODIPY-verapamil, suggesting that engagement of the wild-type Q725 in a hydrogen bond is inhibitory for the transport mechanism. To test transport of unmodified taxol, stable expression of Q347/725A and the triple mutant was engineered and shown to confer equivalent resistance to the drug as the wild-type transporter, further indicating that none of these potential hydrogen bonds between transporter and transport substrate are critical for function of ABCB1. The implications of the data for plasticity of the drug binding pocket are discussed.

Antibiotic inefficacy in treating bacterial infections is largely studied in the context of developing resistance mechanisms. However, little attention has been paid to combined diseases mechanisms, interspecies pathogenesis and the resulting impact on antimicrobial treatment. This review will consider the co-infections of Salmonella and Schistosoma mansoni. It summarises the protective mechanisms that the pathophysiology of the two infections confer, which leads to an antibiotic protection phenomenon. This review will elucidate the functional characteristics of the gut microbiota in the context of these co-infections, the pathogenicity of these infections in infected mice, and the efficacy of the antibiotics used in treatment of these co-infections over time. Salmonella-Schistosoma interactions and the mechanism for antibiotic protection are not well established. However, antimicrobial drug inefficacy is an existing phenomenon in these co-infections. The treatment of schistosomiasis to ensure the efficacy of antibiotic therapy for bacterial infections should be considered in co-infected patients.

Enhanced permeation retention (EPR) was a significant milestone discovery by Maeda et al. paving the road for the emerging nanomedicine as a powerful tool in the fight against cancer. Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE-5) used for treatment of erectile dysfunction (ED) through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. Overexpression of PDE-5 was reported in lung, colon, metastatic breast cancers and bladder squamous carcinoma. Accordingly, there has been a growing interest in using sildenafil as monotherapy or chemoadjuvant in EPR augmentation and management of different types of cancer. Sildenafil had been reported to increase the sensitivity of tumor cells of different origins to the cytotoxic effect of chemotherapeutic agents with augmented apoptosis mediated through inducing the expression of Bad and Bax proapoptotic proteins. It was also reported that the use of sildenafil prior to the administration of Doxorubicin (DOX) increased its EPR-related concentration in breast cancer tissues by 2 folds. Further, a substantial reason of anticancer chemotherapeutic failure is due to multidrug resistance (MDR), exacerbated by the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCCs. Sildenafil has demonstrated inhibitory effects on the efflux activity of ABCC4, ABCC5, ABCB1, and ABCG2, ultimately reversing MDR caused by these transporters. In this review, we critically examine the overall potential of sildenafil in enhancing EPR-based anticancer drug delivery pointing up the outcome of the most important related preclinical and clinical studies.

High-throughput screening technologies continues to produce large amounts of multiomics data from different populations and cell types for various diseases, such as cancer. However, analysis of such data encounters difficulties due to cancer heterogeneity, further exacerbated by human biological complexity and genomic variability. There is a need to redefine the drug discovery development pipeline, bringing an Artificial Intelligence (AI)-powered informational view that integrates relevant biological information and explores new ways to develop effective anticancer approaches. Here, we show SynPred, an interdisciplinary approach that leverages specifically designed ensembles of AI-algorithms, links omics and biophysical traits to predict synergistic anticancer drug synergy. SynPred exhibits state-of-the-art performance metrics: accuracy – 0.85, precision – 0.77, recall – 0.75, AUROC – 0.82, and F1-score - 0.76 in an independent test set. Moreover, data interpretability was achieved by deploying the most current and robust feature importance approaches. A simple web-based application available online at http://www.moreiralab.com/resources/synpred/ was constructed to predict synergistic anticancer drug combinations requiring only the upload of the two drug SMILES to be tested, allowing easy access by non-expert researchers.

The natural product elaiophylin is a macrodiolide with broad biological activities. However, no direct target of elaiophylin in eukaryotes has been described so far, which hinders a systematic explanation of its astonishing activity range. We recently showed that the related conglobatin A, a protein-protein interface inhibitor of the interaction between the N-terminus of Hsp90 and its cochaperone Cdc37, blocks cancer stem cell properties by selectively inhibiting K-Ras4B but not H-Ras. Here we elaborate that elaiophylin likewise disrupts the Hsp90/ Cdc37 interaction, without affecting the ATP-pocket of Hsp90. Similar to conglobatin A, elaiophylin decreased expression levels of the Hsp90 client HIF1⍺, a transcription factor with various downstream targets, including galectin-3. Galectin-3 is a nanocluster scaffold of K-Ras, which explains the K-Ras selectivity of Hsp90 inhibitors. In agreement with this K-Ras targeting and the potent effect on other Hsp90 clients, we observed with elaiophylin treatment a submicromolar IC50 for MDA-MB-231 3D spheroid formation. Finally, a strong inhibition of the same cells grown in the chorioallantoic membrane (CAM) microtumor model was determined. These results suggest that several other macrodiolides may have the Hsp90/ Cdc37 interface as a target site.

Cancer is one of the health concerns in modern societies. The application of nanotechnology in medical sciences has created new possibilities for the diagnosis, imaging and the treatment of tumors in humans. The present article reviews the application of marine-based gold nanoparticles in diagnosing and treating cancer. The main data were collected from research article on the application of different marine-based gold nanoparticles in detecting and imaging cancer cells as well as in drug delivery system in treatment of cancer. Chitosan is the most used marine natural compound used to fabricate gold nanocomposites and the most reported application of this type of nano-composites is related to drug delivery system. Despite the excellent anticancer potential of different marine natural products, less studies have been conducted on the use of their compositions with gold nanoparticles in cancer therapy than other materials. Moreover, most reports available in this filed are related to their application as a drug delivery system not anticancer drug. In general, there are still challenges and limitations to the use of nanoparticles in medicine, it is hoped that in the near future nanoparticles will create a dramatic revolution not only in oncology but also in medicine.

Iloperidone (ILO) is a second-generation antipsychotic drug and a first-line treatment approved by USFDA in May 2009. Iloperidone belongs to Biopharmaceutical Classification Systems (BCS) class II; thus, it is poorly water-soluble, highly permeable, and has pH-dependent solubility. Cyclodextrins and their derivatives have a wide range of applications in different formulations due to their complexation ability, which improves the solubility, stability, safety, and bioavailability of a drug. We have tried the complexation of iloperidone with sulfobutyl ether-β-cyclodextrin (SEβCD) to improve its solubility and dissolution. Complexation was done by the kneading method. The characterization of the SEβCD complexes with Iloperidone was done by FTIR, differential scanning calorimetry (DSC), saturation solubility, etc. A multimedia dissolution of the complex was carried out and compared with the plain drug. A significant improvement in drug release was found from SEβCD complexes in all media when compared with the drug alone.

Objectives: The mechanism of action of drugs that depress the central nervous system (CNS) was unknown until molecular pharmacology discovered each drug's exact role. The benefit of knowing the mechanism of action is to design a new drug that could have the same efficacy as the prototype drug but with fewer side effects. Some of the available CNS depressant drugs that were abused or illegally used could be modified to make them used medically. Methods: We reviewed various published articles in PubMed and Google Scholar that focused on CNS depressants' molecular pharmacology.Results: It was clear that at specific plasma concentrations of ethyl alcohol showed almost same mode of action of propofol by targeting the extrasynaptic GABA-A receptors, which causes tonic GABAergic inhibition. Besides, the High affinity of some benzodiazepines (e.g., midazolam) to α1 subunit of GABA-A receptor causes sedative, hypnotic, amnesic, and some antiepileptic effects; however, some other benzodiazepines (e.g., diazepam) have high affinity to α3 subunits, which causes anxiolytic, muscle relaxant, and strong antiepileptic effects. The CB1 receptor partial agonism effect of tetrahydrocannabinol has a sedative advantage over full agonism due to desensitization of CB1 receptors. Conclusion: From the molecular pharmacology prospect, it is possible to design new drugs with more specific CNS depressants effect and fewer side effects by targeting particular receptors with a precise reaction.

Antibiotic resistance (ABR) is an emerging global threat to public health. Substantial evidence has indicated that community pharmacists (CPs) can play a critical role in managing the ever-increasing threat of antibiotic resistance. The study aimed to determine the knowledge, attitude, and practices of CPs (n=180) towards antibiotics and antibiotic resistance as well as to improve the rational use of antibiotics. Two phases of mixed methods (quantitative and qualitative) online study were conducted in Pakistan from August 2019 to March 2020 by using validated questionnaires and semi-structured interview data. Different statistical methods were used to tabulate the quantitative data whereas inductive thematic analysis was conducted to categorize themes from the qualitative data and draw conclusions. Approximately 64.4% were male (mean: 29-33 years old). Overall, CPs had good knowledge of and were familiar with superbugs and their roles in ABR (65.6%, Median=1, IQR=1) although they were poor in differentiating some antibiotic groups with their respective ABR patterns (31.1%, Median=1, IQR=1). Most CPs have a positive attitude towards antibiotics with most (90.0%) having identified ABR as a critical issue in public health (Median=1, IQR=0). Overall, CPs' practices towards antibiotics were reasonable where they tend to educate patients about the rational use of antibiotics (52.8%, Median=1, IQR=1). Two main themes (antibiotics and counseling of patients) were related to self-medication with while educational interventions are the sub-theme. ABR is multifactorial where the subthemes related to budget, time constraints incompetent staff, the absence of CPs, the lack of training, enforcement of laws and regulations are the need of the hour in Pakistan. Effective antibiotic stewardship programs, patient education, and awareness campaigns about antibiotics and ABR along with training of the CPs are important factors that have to be addressed in a timely manner.

This review will explore the four major pillars required for design and development of an saRNA vaccine: antigen design, vector design, non-viral delivery systems, and manufacturing (both saRNA and lipid nanoparticles (LNP)). In will report on the major innovations, preclinical and clinical data reported in the last five years and will discuss future prospects.

Recently, the outbreak of coronavirus disease 2019 (COVID-19) is threatening human health globally. There is a dire need to find potential therapeutic agents. Angiotensin converting enzyme 2 (ACE2), as an entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is considered as potential therapeutic target in COVID-19 pandemic. Here, our bioinformatics analysis revealed that the biological function of ACE2 was correlated with regulation of blood pressure and mediation of SARS-CoV-2 entry into host cells. Ten ACE2 cooperative proteins were identified by using STRING with a high score. ACE2 expressed highly in the small intestine, testis, and kidney. The level of ACE2 expression in tumor tissues varies in different types of cancers compared with that in normal tissues. It was worth noting that the expression level of ACE2 in the tumor has no effect on patient survival. MiRNA hsa-miR-942-5p, and three transcription factors (TFs) including Signal transducer and activator of transcription 4 (STAT4), Estrogen related receptor α (ESRRA), and Signal transducer and activator of transcription 3 (STAT3) were selected as novel ACE2 regulators. Moreover, nine potential therapeutic drugs were predicted by two online databases. Thus, our research may expand the overall view of ACE2 in COVID-19 treatment.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, has been declared by the World Health Organization (WHO) as a pandemic. Unfortunately, finding a vaccine or developing drugs from the scratch is a time-consuming luxury given the widespread and high fatality rates of the virus. In the short term, repurposing of drugs already in use seem to be the most rational step to quickly and effectively curb the virus. Several antiviral agents had been proposed as possible remedies, but the 4-aminoquinolines, Chloroquine (CHQ) and hydroxychloroquine (HCHQ) appear to be generating more interest. They are generic, cheaply available and have proven efficacy against malaria parasites in Africa. The human immunodeficiency virus (HIV), on the other hand, targets the immune system thereby reducing the patient’s ability to fight infections. Sadly, 68% of the global HIV burden occur in Africa. It is therefore anticipated that incidence of severe forms of COVID-19 could occur in Africa because of associated endemic conditions that compromise the immune system. With CHQ and HCHQ being considered for clinical use against COVID-19, there is a need to highlight their potential merits and confounding variables in the subgroup of patients with or without HIV.

While the COVID-19 pandemic advances, the scientific community struggles in the search for treatments. Several improvements have been made, including the discovery of clinical efficacy of chloroquine (CQ) in COVID-19 patients, but the effective treatment protocols are still missing. In order to find novel treatment options many scientists utilize the in silico approach to identify compounds that could interfere with the key molecules involved in entrance, replication, or dissemination of the SARS-CoV-2. However, most of the identified molecules are currently not available as pharmacological agents, and assessing their safety and efficacy could take many months. Here, we took a different approach based on the proposed pharmacodynamic model of CQ in COVID-19. The main mechanism of action responsible for the favourable outcome of COVID-19 patients treated with CQ seems to be related to pH modulation-mediated effect on the endolysosomal trafficking, a characteristic of chemical compounds often called lysosomotropic agents because of the physico-chemical properties that enable them to passively diffuse through the endosomal membrane and undergo protonation-based trapping in the lumen of the acidic vesicles. In this review, we discuss lysosomotropic and lysosome targeting drugs that are already in clinical use and are characterized by good safety profiles, low cost, and wide availability. We emphasize that some of these drugs, in particular azithromycin and other macrolide antibiotics, indomethacin and some other non-steroidal anti-inflammatory drugs, proton pump inhibitors, and fluoxetine could provide additional therapeutic benefits in addition to the potential antiviral effect that still has to be confirmed by well-controlled clinical trials. As some of these drugs, mostly antibiotics, were already empirically used in the treatment of COVID-19, we encourage our colleagues all over the world to publish patient data so potential efficacy of these agents can be evaluated in the clinical context and rapidly implemented in the therapeutic protocols if the beneficial effect on clinical outcome is observed.

Background: Diabetic foot ulcers are an increasingly common complex problem and are associated with a very considerable health care burden. Diabetic foot ulcer with Alcaligenes faecalis infection is rarely reported in the literature. We report a case series of diabetic foot ulcer with Alcaligenes faecalis infection treated at our facility. Methods: We conducted a retrospective analysis of all patients with diabetic foot ulcer with Alcaligenes faecalis infection seen from January 2014 to April 2019. We analyzed the clinical characteristics, ulcer lesion classification, comorbidities, prior intravenous antibiotic use within three months, wound culture, antibiotics sensitivity test, and clinical outcomes of these patients. Results: Eight cases of diabetic foot ulcer with Alcaligenes faecalis infection were seen in five males and three females. The mean age was 54.6 years. All patients had other comorbidities, and all ulcer lesions were of chronic duration ( more than 14 days ). All wound cultures revealed polymicrobial infection, with two cases of diabetic foot with extensive-drug resistant Alcaligenes faecalis infection found in 2019. All patients needed intravenous antibiotic therapy and surgical interventions for the chronic ulcer lesion. The wound failed to heal in three patients. Conclusions: All diabetic foot ulcers with Alcaligenes faecalis infection were of chronic duration ( more than 14 days ) and had polymicrobial infection. Extensive-drug resistant Alcaligenes faecalis emerged in 2019. Definitive antibiotic therapy is necessary for all infected wounds and should be based on both the culture results and susceptibility data. All patients will need appropriate wound care, and most will need rapid surgical intervention for an optimal outcome.

Specialized, reductionist, and linear approaches are applied in clinical research; they are based on linear logic and used towards therapeutic molecule-based targets. However, those approaches do not consider a systemic vision that describes the remote cause of the pathogenic activation. We propose new theoretical and practical methods for the next drug generation development. Self-organization, network structure, hierarchical organization, non-linearity, feedback circuits, reactions to information, and the view of drugs as information clarify the existing pharmacological methods. We suggest a perspective and hierarchical vision of the human organism based on six levels (mechanic and structural; metabolic; bodily dynamic; emotional, cognitive, spiritual). The therapy should restore the self-organization of every level using the “intelligent” modulation of the network responses. Multi-targeted drugs should act on the remote cause of the pathogenic cascade and be administered based on personal variability and networks. This approach may help the development of individualized, precise, and integrated medicine.

Antibiotic failure is one of the most worrying health problems worldwide. Nowadays we are facing an international crisis where several issues are involved: new antibiotics are not being discovered any longer, resistance mechanisms become spread in nearly every clinical isolate of bacteria and the appearance of recurrent infections caused by persistent bacteria complicates the overcoming of infections. In this context, it has been explored new anti-infectious strategies against MDR and persistent bacteria as well as the rescue of FDA-approved compounds (drug repurposing). Among the highlighted new anti-infectious strategies we find anti-microbial peptides, anti-virulence compounds, phage therapy and new molecules. On the other hand, as drugs of repurposing that have been described, we have anti-inflammatory compounds, anti-psychotics, anti-helmintic drugs, anti-cancerous and statins.

The key issue in the post-genomic era is how to systematically describe the association between small molecule transcripts or translations inside cells. With the rapid development of high-throughput “omics” technologies, the achieved ability to detect and characterize molecules with other molecule targets opens up the possibility of investigating the relationships between different molecules from a global perspective. In this article, a Molecular Associations Network(MAN) is constructed and comprehensively analyzed by integrating the associations among miRNA, lncRNA, protein, drug, and disease, in which any kind of potential associations can be predicted. More specifically, each node in MAN can be represented as a vector by combining two kinds of information including the attributes of the node itself (e.g. sequences of ncRNAs and proteins, semantics of diseases and molecular fingerprints of drugs) and the manner of the node in the complex network (associations with other nodes). Random Forest classifier is trained to classify and predict new interactions or associations between biomolecules. In the experiment, the proposed method achieves a superb performance with 0.9735 AUC in 5-fold cross-validation, which show that the proposed method can provide new insight for exploration of the molecular mechanisms of disease and valuable clues for disease treatment.

Three-dimensional (3D) cell culture is considered more clinically relevant in mimicking the structural and physiological conditions of tumors in vivo compared to two-dimensional cell cultures. In recent years, high-throughput screening (HTS) in 3D cell arrays has been extensively used for drug discovery because of its usability and applicability. Herein, we developed a microfluidic spheroid culture device (μFSCD) with a concentration gradient generator (CGG) that enabled cells to form spheroids and grow in the presence of cancer drug gradients. The device is composed of concave microwells with several serpentine micro-channels which generate a concentration gradient. Once the colon cancer cells (HCT116) formed a single spheroid (approximately 120 μm in diameter) in each microwell, spheroids were perfused in the presence of the cancer drug gradient irinotecan for 3 days. The number of spheroids, roundness, and cell viability, were inversely proportional to the drug concentration. These results suggest that the μFSCD with a CGG has the potential to become an HTS platform for screening the efficacy of cancer drugs.

Cone snails (genus Conus) are venomous marine snails that inject prey with a lethal cocktail of conotoxins, small, secreted, cysteine-rich peptides. Given the diversity and often high affinity for their molecular targets, consisting of ion channels, receptors or transporters, many conotoxins have become invaluable pharmacological probes, drug leads and therapeutics. Transcriptome sequencing of Conus venom glands followed by de novo assembly and homology-based toxin identification and annotation is currently the state-of-the-art for discovery of new conotoxins. However, homology-based search techniques, by definition, can only detect novel toxins that are homologous to previously reported conotoxins. To overcome these obstacles for discovery we have created ConusPipe, a machine learning tool that utilizes prominent chemical characters of conotoxins to predict whether a certain transcript in a Conus transcriptome, which has no otherwise detectable homologs in current reference databases, is a putative conotoxin. By using ConusPipe on RNASeq data of 10 species, we report 5,230 new putative conotoxin transcripts that have no homologues in current reference databases. 893 of these were identified by at least 3 out of 4 models used. These data significantly expand current publicly available conotoxin datasets and our approach provides a new computational avenue for the discovery of novel toxin families.

Hospital-based adverse drug reaction (ADR) monitoring and reporting programs intend to identify and quantify the risks associated with the use of drugs. To examine the causality, preventability and severity of ADR in a hospital setting; a prospective cohort study on spontaneous ADR reporting was conducted from December 2015 to May 2016. Incidence of ADRs, causality, type, severity and preventability were assessed using necessary assessment scales. The study included 3157 hospitalized individuals, in whom 51 ADRs were detected among 49 patients. The overall incidence of suspected ADRs was found to be 1.6%. According to the causality assessment, most of the ADRs reported were probable (n = 26, 51.0%), and type A (augmented/pharmacological) reactions (n = 39, 76%) were the most common type of ADR found. The majority of ADRs were moderate to severe (n = 35, 68.6%), of which 37.3% were found to be potentially preventable. Predictability was observed in 28 (54.9%) reported ADRs. The drugs most frequently associated with ADRs were antibiotics, antiepileptics and antihypertensives. This feasibility study was able to highlight the clinical pharmacist’s role in ADR monitoring service and create awareness about the way it could be done to promote safer drug use. Similar ADR reporting programs are necessary to educate and to improve awareness among the healthcare professionals in developing countries.

The vertebrate annexin superfamily (AnxA) consists of 12 calcium (Ca2+) and phospholipid binding proteins which share a high structural homology. In keeping with this hallmark feature, annexins have been implicated in the Ca2+-controlled regulation of membrane events. In this review, we discuss several themes of potential therapeutic value, namely the regulation of the immune response and the control of tissue homeostasis, that repeatedly surface in the annexin action profile. Our aim is to identify and discuss those annexin properties which might be exploited from a translational science and specifically clinical point of view.

Oral cancer is a major public health burden worldwide. The lack of biomarkers for early diagnosis has increased the difficulty in managing this disease. Recent studies have reported that neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, is upregulated in various tumors. In our study we found that NGAL was significantly downregulated in primary malignant and metastatic tissues of oral cancer compared to normal tissues. The downregulation of NGAL was strongly correlated with the degree of differentiation and stage (I-IV), and can serve as a prognostic biomarker for oral cancer. Tobacco carcinogens were also found to be involved in the downregulation of NGAL. Mechanistic studies revealed that knockdown of NGAL increased oral cancer cell proliferation, survival, and migration, and also induced resistance against cisplatin. Silencing of NGAL activated mTOR signaling and reduced autophagy by the LKB1-AMPK-p53-Redd1 signaling axis. Moreover, cyclin-D1, Bcl-2, and MMP-9 were upregulated, and caspase-9 was downregulated, suggesting that silencing of NGAL increases oral cancer cell proliferation, survival, and migration. Thus, from our study it is evident that downregulation of NGAL activates the mTOR pathway and helps in the progression of oral cancer.

Chitosan is a cationic polysaccharide usually obtained by alkaline deacetylation of chitin poly(N-acetylglucosamine). It is biocompatible, biodegradable, mucoadhesive and non-toxic. These excellent biological properties make chitosan a good candidate for a platform in developing drug delivery systems having improved biodistribution, increased specificity and sensitivity, and reduced pharmacological toxicity. In particular, chitosan nanoparticles are found to be appropriate for non-invasive routes of drug administration: oral, nasal, pulmonary and ocular routes. These applications are facilitated by the absorption-enhancing effect of chitosan. Many procedures for obtaining chitosan nanoparticles have been proposed. Particularly, the introduction of hydrophobic moieties into chitosan molecules by grafting to generate a hydrophobic-hydrophilic balance promoting self-assembly is a current and appealing approach. The grafting agent can be a hydrophobic moiety forming micelles that can entrap lipophilic drugs or it can be the drug itself. Another suitable way to generate self-assembled chitosan nanoparticles is through the formation of polyelectrolyte complexes with polyanions. This paper reviews the main approaches for preparing chitosan nanoparticles by self-assembly through both procedures and illustrates the state of the art of their application in drug delivery.

Nanoparticles have been used as a novel drug delivery system. Drug-incorporated nanoparticles for local delivery might optimize the efficacy and minimize the side effects of drugs. The efficacy and safety of intratracheal administration of prostacyclin analog (beraprost)-incorporated nanoparticles and imatinib, a PDGF-receptor tyrosine kinase inhibitor, -incorporated nanoparticles in Sugen-hypoxia-normoxia or monocrotaline rat models of PAH and in human PAH-pulmonary arterial smooth muscle cells have been reported. The use of inhaled drug-incorporated nanoparticles might be a novel approach for treatment of PAH.

A simple, isocratic and robust RP-HPLC method for the analysis of azithromycin was developed, validated and applied for the analysis of bulk samples, tablets and suspensions. The optimum chromatographic conditions for separation were established as mobile phase comprising of acetonitrile-0.1M KH₂PO₄ pH 6.5-0.1M tetrabutyl ammonium hydroxide pH 6.5-water (25:15:1:59% v/v/v/v) delivered at a flow rate of 1.0 ml/min. The stationary phase consisted of reverse-phase XTerra^® (250 mm× 4.6 mm i.d., 5 µm particle size) maintained at a temperature of 43 °C with a UV detection at 215 nm. The method was found to be linear in the range 50-150% (r²=0.997). The limits of detection and quantification were found to be 0.02% (20 µg) and 0.078% (78 µg) respectively with a 100.7% recovery of azithromycin. Degradation products of azithromycin in acidic and oxidative environments at 37 °C were resolved from the active pharmaceutical ingredient and thus the method is fit for the purpose of drug stability confirmation.

In the dynamic landscape of drug discovery, Computer-rAided Drug Design (CADD) emerges as a transformative force, bridging the realms of biology and technology. This paper overviews CADD's historical evolution, categorization into structure-based and ligand-based approaches, and its crucial role in rationalizing and expediting drug discovery. As CADD advances, incorporating diverse biological data and ensuring data privacy become paramount. Challenges persist, demanding the optimization of algorithms and robust ethical frameworks. Integrating Machine Learning and Artificial Intelligence amplifies CADD's predictive capabilities, yet ethical considerations and scalability challenges linger. Collaborative efforts and global initiatives, exemplified by platforms like Open Source Malaria, underscore the democratization of drug discovery. The convergence of CADD with personalized medicine offers tailored therapeutic solutions, though ethical dilemmas and accessibility concerns must be navigated. Emerging technologies like quantum computing, immersive technologies, and green chemistry promise to redefine the future of CADD. The trajectory of CADD, marked by rapid advancements, anticipates challenges in ensuring accuracy, addressing biases in AI, and incorporating sustainability metrics. The paper concludes by highlighting the need for proactive measures in navigating the ethical, technological, and educational frontiers of CADD to shape a healthier, brighter future in drug discovery.

The target of an antibody plays a significant role in the success of antibody-based therapeutics and diagnostics, and to an extent, that of vaccine development. This importance is focussed on the target binding site – epitope, where epitope selection as a part of design thinking beyond traditional antigen selection using whole cell or whole protein immunisation can positively impact success. With purified recombinant protein production and peptide synthesis to display limited/selected epitopes, intrinsic factors that can affect the functioning of resulting antibodies can be more easily selected for. Many of these factors stem from the location of the epitope that can affect accessibility of the antibody to the epitope at a cellular or molecular level, direct inhibition of target antigen activity, conservation of function despite escape mutations, and even non-competitive inhibition sites. Through the incorporation of novel computational methods for predicting antigen changes to model-informed drug discovery and development, superior vaccines and antibody-based therapeutics or diagnostics can now be more easily designed to mitigate failures. With detailed examples, this review highlights the new opportunities, factors and methods of predicting antigenic changes for consideration in sagacious epitope selection.

Ecological footprint calculators are digital tools that help individuals calculate their environmental or climate impact, with the aim of stimulating pro-environmental behaviour change. These footprint calculators typically take an information-provision approach, but this strategy assumes that increased levels of knowledge result in increased levels of pro-environmental behaviour (i.e., a reduced footprint). This is not a given – existing literature on the relationship between environmental knowledge and pro-environmental behaviour is inconclusive, and this relationship may be different from that of environmental knowledge and ecological footprint. As such, we investigated the relationship between environmental knowledge and ecological footprint as estimated by a footprint calculator. 448 Dutch participants completed an online survey, including an ecological footprint calculator. We found no evidence for a relationship between environmental knowledge and ecological footprint calculator outcome. Rather, an exploratory analysis of our data showed that environmental values were more important predictors of ecological footprint. The finding that increased levels of knowledge are not related to a reduced ecological footprint suggests that calculators would do well to move beyond information provision, and employ additional behaviour change strategies. Based on our exploratory analysis, we provide several concrete examples of potential strategies.

Alzheimer’s disease (AD) causes dementia and memory loss in the elderly. Deposits of beta-amyloid peptide and hyperphosphorylated tau protein are present in AD’s brain. A filtrate of Helicobacter pylori’s culture was previously found to induce hyperphosphorylation of tau in vivo, suggesting that bacterial exotoxins could permeate the blood brain barrier and directly induce tau’s phosphorylation. H. pylori, which infects ~60% of the world population and causes gastritis and gastric cancer, produces a pro-inflammatory urease (HPU). Here the neurotoxic potential of HPU was investigated in cultured cells and in rats. SH-SY5Y neuroblastoma cells exposed HPU (50-300 nM) produced reactive oxygen species (ROS) and had an increased [Ca2+]i. HPU-treated BV-2 microglial cells produced ROS, cytokines IL-1β and TNF-α, expressed Iba1 and showed reduced viability, consistent with a neurotoxic effect of HPU. Rats received daily i.p. HPU (5 µg) for 7 days. Hyperphosphorylation of tau at Thr205, Ser199 and Ser396 sites was seen in hippocampal homogenates of treated rats, with no alterations in total tau or GSK-3b levels. HPU was not detected in the brain homogenates. Behavioral tests were performed to assess cognitive impairments. Our findings support previous data suggesting an association between infection by H. pylori and tauopathies such as AD, possibly mediated by its urease.

Chronic mountain sickness (CMS) poses a significant health risk to individuals who rapidly ascend to high altitudes, potentially endangering their lives. Inorganic nanoparticles offer an effective means of transporting and delivering drugs, protecting nucleic acids from nuclease degradation, and mediating the expression of target genes in specific cells. These nanoparticles are almost non-toxic, easy to prepare and store, possess a large surface area, exhibit good biocompatibility and degradability, and maintain good stability. They can be utilized in the treatment of CMS to enhance the therapeutic efficacy of drugs. This paper provides an overview of the impact of inorganic nanomaterials on CMS, discussing their roles as nanocarriers and their potential in CMS treatment. It aims to present novel therapeutic strategies for the clinical management of CMS and summarizes the relevant pathways through which nanomaterials contribute to plateau disease treatment, providing a theoretical foundation for future clinical research.

Next-generation sequencing(NGS) for HIV drug resistance(DR) testing has an increasing number of applications for detection of Low-abundance drug resistant variants(LA-DRVs) as its features of quasispecies. However there is less information on detection performance in DR detection with NGS.To determine the feasibility of NGS technology in LA-DRVs detection for HIV-1 pre-treated patients.In this study,80 pre-treated patients’ samples accepted both NGS and Sanger sequencing(SS) in HIV-1 drug resistance testing. The results show that NGS presents higher sensitivity in mutation sites discovery at 5% threshold. NGS shows a satisfactory consistency comparing with SS in both protease inhibitors(PIs) and Integrase inhibitor(INSTIs), more than 90%. But worse consistency in Nucleotide reverse transcriptase inhibitors(NRTIs), only ranging from 61.25%-87.50%. The consistency of Non-nucleotide reverse transcriptase inhibitors(NNRTIs) between NGS and SS was around 85%. NGS shows the highest sensitivity of 91.3% at 5% threshold. The application of NGS technology in HIV-1 genotype resistance detection in different populations infected with HIV needs more documents and to be confirm further.

Introduction: Pharmaceutical tablets are solid forms administrated orally and they constitute 80% of the market because of its best stability and ease of large-scale production, adherence and treatment. The Brazilian Legislation establishes that for a drug to be registered as a similar or generic drug is necessary to verify the pharmaceutical equivalence in relation to the reference drug, indicated by ANVISA, through quality control tests, ensuring that the drug is approved with satisfactory quality. Objective: to evaluate the reference, generic and similar glibenclamide tablets through quality control tests, comparing the results with each other and relate clinical impacts on the patient in the face of changes in the quality control of medicines. Methodology: tests of average weight, friability and disintegration were done, according to the Brazilian Pharmacopoeia VI Edition, in uncoated tablets of Glibenclamide 5mg Reference (Daonil), Generic (Glibenclamide) and Similar (Glionil), and the results obtained were compared with the that advocates the scientific literature. Results: Data referring to the average weight: Reference 0.1591g, Generic 0.1002g and Similar 0.0996g; For friability: Reference value 0.54%, Generic value 0.49% and Similar value 0.28%. The disintegration tests showed the following times: Reference 35 seconds, Generic 29 seconds and Similar 33 seconds. Conclusion: the tests to which the glibenclamide tablets were submitted showed results within the parameters established by the Brazilian Pharmacopoeia.

The authors propose a novel approach for a comprehensive evaluation of neuroprotective effects using both in vitro and in vivo methods. This approach allows for the initial screening of numerous newly synthesized chemical compounds and substances from plant and animal sources while preserving animal life. In vitro techniques, including mitochondrial suspensions and neuronal cell cultures, enable assessment of neuroprotective activity, which can be challenging in intact organisms. The preliminary methods help outline the neuroprotection mechanism depending on the neurodestruction agent. The authors have validated a model of acute cerebrovascular accident, which simulates key cerebrovascular phenomena such as reduced cerebral blood flow, energy deficit, glutamate-calcium excitotoxicity, oxidative stress, and early gene expression. A significant advantage of this model is its ability to reproduce the clinical picture of cerebral ischemia: impaired motor activity, signs of neurological deficits (paresis, paralysis, etc.), as well as disturbances in attention, learning, and memory. Crucial to this approach is the selection of biochemical, molecular, and cellular markers to evaluate nerve tissue damage and characterize potential neuroprotective agents. Additionally, a comprehensive set of molecular, biochemical, histological, and immunohistochemical methods is proposed for evaluating neuroprotective effects and underlying mechanisms of potential pharmaceutical compounds.

Anticonvulsant drugs are widely used in the management of epilepsy and other neurological disorders. However, their concomitant use with other medications can lead to significant drug interactions, impacting both efficacy and safety. This article aims to provide a comprehensive overview of common anticonvulsant interactions with other frequently used drugs. It discusses the mechanisms of these interactions, their clinical implications, and strategies for managing them. The article also highlights the importance of monitoring and patient education in minimizing adverse outcomes.

Long COVID is a phenomenon in which individuals experience persistent symptoms after recovering from COVID-19. The symptoms are discovered to be unique for every individual and can affect multiple organs systems in the body. This study aims to identify effective natural remedies for long COVID by analyzing hub genes associated with the symptoms of the condition and evaluating the repurposed drugs catered and used for treating the symptoms of long COVID. The most common and prevalent symptoms of long COVID were identified; Fatigue, Shortness of Breath, Loss of Smell, Headache, Brain Fog, Chest Pain, Insomnia, Heart Palpitations, Dizziness, Joint Pain, Depression, Anxiety, Tinnitus, Loss of Appetite. Hub genes for each of the symptoms provided an insight on the key biological pathways of the symptom. Repurposed drugs identified, provided the template to identify the natural compounds with similar structure as a potential therapeutic drug. The natural compounds were retrieved using fingerprint search of the repurposed drugs from the NPASS Database. The findings of this study suggest several natural remedies for each symptom based on the molecular docking of the hub gene and natural compound using iGEMDOCK. The identified natural remedies may hold promise in treating long COVID, but further research is required to explore the efficacy and effectiveness of the proposed natural compounds. The results of the study pose important implications for the development of effective treatments for long COVID.

This review critically evaluates the role of Antibody-drug conjugates (ADCs) in the treatment of urothelial cancer, exploring their therapeutic potential and addressing the scientific and clinical challenges encountered in the development of these agents. It also discusses the recent approvals and clinical trials that are shaping the future of ADC therapy in this field. Through a detailed examination of the mechanism of action of ADCs, including the bystander effect, this paper aims to highlight both the successes and the limitations of these drugs in clinical settings. The main objective of this work is to provide a thorough overview of the current state of ADCs in urothelial cancer treatment, elucidating how these drugs can offer improved outcomes for patients. By discussing the broader implications of ADC technology and its integration into existing treatment paradigms, this review outlines the next steps in research and application necessary to overcome the existing challenges and harness the full potential of ADCs in cancer therapy.

Curcumin is a nutraceutical known to have numerous medicinal effects including anticancer activity. However, due to its poor water solubility and bioavailability, the therapeutic impact of curcumin against cancer, especially breast cancer, has been constrained. Encapsulating curcumin into chitosan nanoparticles (CHNPs) is an effective method to increase its bioavailability as well as antitumorigenic activity. In the present study, the effect of curcumin encapsulated CHNPs (Cur-CHNPs) on cell migration, targeted homing and tumour growth was examined using in vitro and in vivo breast cancer models. Cur-CHNPs possessed monodispersed nature with long term colloidal stability, and demonstrated significant inhibition of cell viability in vitro, which was potentiated by 5-fluorouracil (5-FU). Outcomes of the in vivo imaging studies confirmed effective tumour targeting and retention ability of Cur-CHNPs, thereby suppressing breast tumour growth in mice models. Overall, the results demonstrated that Cur-CHNPs, could be an effective candidate drug formulation for management of breast cancer.

Carbon nanodots (CNDs) have garnered significant attention as viable drug delivery vehicles in recent years, especially in the field of phytomedicine. Although there is much promise for therapeutic applications with phytomedicine, its effectiveness is frequently restricted by its low solubility, stability, and bioavailability. This paper offers a thorough synopsis of the developing field of phytomedicine drug delivery based on CND. It explores CND synthesis processes, surface functionalization strategies, and structural and optical characteristics. Additionally, the advantages and difficulties of phytomedicine are examined, with a focus on the contribution of drug delivery methods to the increased effectiveness of phytomedicine. The applications of CNDs in drug delivery are also included in the review, along with the mechanisms that underlie their improved drug delivery capabilities. Additionally, it looks at controlled release methods, stability augmentation, and phytomedicine loading tactics onto CNDs. The potential of polymeric carbon nanodots in drug delivery is also covered, along with difficulties and prospective directions going forward, such as resolving toxicity and biocompatibility issues. In summary, the present review highlights the encouraging contribution of CNDs to the field of drug delivery, specifically in enhancing the potential of phytomedicine for therapeutic purposes.

In this work, we report the synthesis of a new thiosemicarbazone-based drug of N'-(di(pyridin-2-yl)methylene)-4-(thiazol-2-yl)piperazine-1-carbothiohydrazide (HL) featuring a thiazole spectator for the efficient coordination with Cu(II) to give [CuCl(L)]2 (1) and [Cu(NO3)(L)]2 (2). Both 1 and 2 exhibit dimeric structures ascribed to the presence of di-2-pyridylketone moieties that demonstrate dual functions of chelation and intermolecular bridging. HL, 1 and 2 are highly toxic against hepatocellular carcinoma cell lines Hep-G2, PLC/PRF/5, and HuH-7, with half maximal inhibitory concentration (IC50) values as low as 3.26 nmol/mL (HL), 2.18 nmol/mL (1), and 2.54 × 10−5 nmol/mL (2) for PLC/PRF/5. While the free ligand HL may elicit its anticancer effect via sequestration of bio-relevant metal ions (i.e. Fe3+ and Cu2+), 1 and 2 are also capable of generating cytotoxic reactive oxygen species (ROS) to inhibit cancer cell proliferation. Our preliminary pharmacokinetic studies revealed that oral administration (per os, PO) of HL has a significantly longer half-life t1/2 of 21.61 ± 9.4 h, nearly doubled as compared to that of the intravenous (i.v.) administration of 11.88 ± 1.66 h, certifying HL as an effective chemotherapeutic drug via PO administration.

Preventing or treating infections at implantation sites where the risk of bacterial contamination is high requires the development of intelligent drug delivery systems. In this work, honeycomb structures as a potential drug carrier were obtained for the first time in a fast, one-step anodization process of titanium grade 4, lasting only 60 seconds. Fourth generation oxide nanotube layers were obtained from an aqueous solution of 0.5% AgNO3 in the voltage range from 50 to 80 at 15(1) °C. The FE-SEM method showed the length of the oxide nanotubes from 1.02(2) µm at 50 V to 230(8) nm at 80 V. The EDS analysis revealed that during anodizing, silver particles are deposited on the Ti G4 up to 2.2(5) wt.%. Electrochemical measurements by open circuit potential and anodic polarization curves methods proved the improvement of in vitro corrosion resistance as a result of Ti G4 anodizing. Assessment of the anodized Ti G4 as gentamicin sulfate carrier carried out using ATR-FTIR and UV-VIS absorption spectroscopy revealed that the obtained oxide nanotube layers can be used for application of drugs directly to the tissue around the implant. This method of application allows full use of the therapeutic dose of the antibiotic used.

Diabetes is one of the metabolic syndromes that demands the great concern affecting millions of people all over the world. Viral infections were also considered as responsible for diabetes. Though, variety of medications for prevention and treatment of diabetes are available, numerous limitations are also prevailing that cannot be neglected. Precise drug-targetability, controlled drug-release, oral bioavailability, minimizing side effects are a few to consider. To address most of these shortcomings of traditional drug-delivery models, nanoformulation has been employed therein a wide range of nanoformulation models are developed. The pharmacology of a drug can be greatly enhanced through nanoformulation models in diabetes treatment in terms of enhanced bioavailability, prolonged and sustained drug-lease, maintain maximum drug concentration in serum, higher intestinal absorption, and protection from enzymatic degradation. In this review work, recently designed nanoformulation models for efficient insulin delivery and the other properties concerning diabetes such as reducing blood glucose level, total cholesterol, triglycerides, lipid profile, wound healing, elevating antioxidant enzymes etc. are discussed. Classification of the nanoformulation models is done based on the nature of the fabricating material employed in nanoformulation. This review may be helpful in designing a more efficient nanoformulation model for diabetes treatment.

Mississippi youth are demographically unique compared to that of the nation. The purpose of this study was to determine the trend of drug use among adolescents of the United States and Mississippi, and to estimate the differences of drug use prevalence as a whole, and by gender and by race. National and Mississippi YRBSS data from 2001 to 2021 were obtained for analysis. Summary statistics, prevalence ratio, and survey Chi-squared tests of independence statistics were generated for the comparison for all students, and by gender and race separately. Trend analysis was conducted using logistic regression combined with joinpoint regression. Six survey questions being studied were: have you ever used marijuana, inhalant, heroin, methamphetamines, injected drugs, and were you offered, sold, or given an illegal drug on school property during the last 12 months. Survey packages in R were used to account for the complex sampling design of YRBSS data. On the national level, all six drug related risk behaviors being studied showed significant decrease from 2001 to 2021. In Mississippi however, only “ever used marijuana” showed a trend of decrease, while three remain unchanged, and two increased. 2021 YRBSS data shows that Mississippi adolescents exhibited significantly higher prevalence of drug use, and are more likely to be offered, sold or given an illegal drug on school property. Our study suggests an urgent need for drug use intervention among Mississippi adolescents. More concerted actions at the community, school and government level are needed for reducing youth drug use and controlling the drug traffic on school property.

M184V is a single-base mutation in the YMDD domain of reverse transcriptase (RT). The M184V resistance-associated mutation is related to virological unresponsiveness to lamivudine (3TC) and emtricitabine (FTC) and induces high-level resistance to these two antiretroviral agents. M184V is rapidly selected in the setting of non-suppressive antiretroviral therapy (ART) and accumulates in the HIV reservoir. There were continuous efforts to evaluate the impact of M184V mutation on the treatment outcomes in people with HIV (PWH). Since lamivudine remains an extensively used part of recommended antiretroviral combinations, M184V is commonly detected in patients with virological failure. ART guidelines do not recommend the use of drugs impacted by resistance-associated mutations as they have been confirmed to comprise a risk factor for virological failure. However, previous authors suggest that 3TC/FTC can remain active even in the presence of M184V. Obtaining the viral resistance profile for each individual both treated or ART-naïve is a key challenge for lifelong treatment management.Given the potential benefits of lamivudine in the ART combinations, the investigation of M184V remains of high interest for clinicians and researchers. This is a review of literature for the challenges in treating both naïve and experienced individuals carrying the M184V resistance mutation, including virological failure, virological suppression, and resistance to ART.

Neurologic symptoms associated with Long COVID result from the persistent infection of SARS-CoV-2 in the nasal neuroepithelial cells, leading to inflammation in the central nervous sys-tem (CNS). As of today, there is no evidence that vaccines or medications can clear the persistent viral infection in the olfactory mucosa. Recently published clinical data demonstrate that only 5% of Long COVID anosmia patients have fully recovered during the past 2 years and 10.4% of COVID patients are still symptomatic 18 months post infection. Our group demonstrated that ep-igallocatechin-3-gallate-monopalmitate (EC16m) nanoformulations possess strong antiviral activ-ity against human coronavirus, suggesting this green tea-derived compound in nanoparticle for-mulations could be developed as an intranasally delivered new drug targeting the persistent SARS-CoV-2 infection, as well as inflammation and oxidative stress in the CNS, leading to resto-ration of neurologic functions. The objective of the current study is to evaluate the mucociliary safety of the EC16m nasal nanoformulations and the efficacy against human coronavirus. Meth-ods: nanoparticle size and Zeta potential were measured using the ZetaView Nanoparticle Tracking Analysis system; mucociliary safety was determined using MucilAir Human Nasal Epi-thelium Model; contact antiviral activity and post-infection inhibition against OC43 viral strain were assessed by TCID50 assay for cytopathic effect on MRC-5 cells. Results: the saline-based EC16 mucoadhesive nanoformulations containing 0.005 to 0.02% w/v EC16m have no significant difference in comparison to saline (0.9% NaCl) on tissue integrity, cytotoxicity, and cilia beat fre-quency. A 5-minute contact inactivated 99.9% of the β-coronavirus OC43. OC43 viral replication was inhibited by >99% after infected MAR-5 cells were treated with one of the formulations. Con-clusion: the saline-based novel EC16m mucoadhesive nasal nanoformulations rapidly inactivated human coronavirus with mucociliary safety measurements comparable to saline, a solution widely used for nasal applications.

Fungal infections caused by Candida spp. are responsible for high hospital morbidity and mortality rates. Therefore, there is a continuous search for new antifungal medicines, particularly ones with anti-Candida activity. This review analyzed articles published between 2002 and 2023 considering the anti-Candida activity of chemical compounds identified or isolated in plants of the Anacardiaceae family. In addition, the in-silico prediction of the isolated compounds described was performed. The analysis of 35 studies showed that extracts, essential oils, and compounds from the anti-Candida activity were frequently determined in vitro using the minimum inhibitory concentration (MIC). The most commonly tested species were Candida albicans, C. tropicalis, C. parapsilosis, C. glabrata, C. krusei, and C. guilliermondii, respectively. Essential oils were the most used form (37% of the studies). The isolated compounds with antifungal effects include cardanol, estragole, trans-anethole, β-caryophyllene, myrcene, catechin-3-o-rhamnoside, β-sitosterol-3-O-glucoside, 24Z-isomasticadienolic acid, oleanolic acid, and oleanolic aldehyde. The in-silico evaluation of those isolated compounds revealed the compounds' drug-likeness and possible antifungal activity. However, some of them showed high toxicity. In conclusion, compounds from the Anacardiaceae family show promise for developing new therapeutic antifungal drugs, especially in combination with conventional antifungals.

Abstract: Lung cancer, characterized by its heterogeneity, presents a significant challenge in ther-apeutic management, primarily due to the development of resistance to conventional drugs. This resistance is often compounded by the tumour’s ability to reprogram its metabolic pathways, a survival strategy that enables cancer cells to thrive in adverse conditions. This review article ex-plores the complex link between drug resistance and metabolic reprogramming in lung cancer, offering a detailed analysis of the molecular mechanisms and treatment strategies. It emphasizes the interplay between drug resistance and changes in metabolic pathways, crucial for developing effective lung cancer therapies. The review examines the impact of current treatments on metabolic pathways and the significance of considering metabolic factors to combat drug resistance. It highlights the different challenges and metabolic alterations in non-small cell lung cancer and small cell lung cancer, underlining the need for subtype-specific treatments. Key signalling pathways, including PI3K/AKT/mTOR, MAPK, and AMPK, have been discussed for their roles in promoting drug resistance and metabolic changes, alongside the complex regulatory networks involved. The article evaluates emerging treatments targeting metabolism, such as metabolic inhibitors, dietary management, and combination therapies, assessing their potential and challenges. It concludes with insights into the role of precision medicine and metabolic biomarkers in crafting personalized lung cancer treatments, advocating for metabolic targeting as a promising approach to enhance treatment efficacy and overcome drug resistance. The review underscores ongoing advancements and hurdles in integrating metabolic considerations into lung cancer therapy strategies.

Hiccups can significantly reduce the quality of life of patients and can occur as a drug side effect. Previous report using the Drug Adverse Event Database revealed sex-specific differences in the incidence of drug-induced hiccups. However, the pathogenesis of drug-induced hiccups remains unknown, and there is limited evidence on its treatment or prevention. This study examined molecular initiating events (MIEs), which are the starting point of adverse events, to investigate the drug-induced pathways of hiccups. We extracted drugs suspected to cause hiccups using FDA Adverse Event Reporting System, a large database on adverse drug reactions. Information on drugs suspected to be associated with hiccups were extracted from the overall population and sex-specific subgroups divided. In each data table, the predicted activity values of nuclear receptors (NRs) and stress response pathways (SPs) for each drug were calculated using the toxicity predictor, a machine-learning model. Univariate analysis extracted NRs and SPs associated with hiccups, and a multivariate analysis was performed to evaluate independent factors. Transforming growth factor-beta and antioxidant response element were considered an independent factor for hiccups in the male and female subgroups, respectively. This report first examined one of the mechanisms of drug-induced hiccups and identified MIEs associated with drug-induced hiccups.

The aberrant glycosylation is a hallmark of cancer progression and chemoresistance. It is also an immune therapeutic target for various cancers. Tunicamycin (TM) is one of the potent nucleo-side antibiotics and an inhibitor of aberrant glycosylation in various cancer cells, including breast cancer, gastric cancer, and pancreatic cancer, parallel with inhibition of cancer cell growth and progression of tumors. Thus, TM can be considered a potent antitumor drug in various cancers and may promote chemosensitivity. Mechanistically, TM impedes the role of the UDP-HexNAc enzyme in the biosynthesis of oligosaccharides, specialized macromolecules instrumental in N-linked glycosylation. Further, like chemotherapies such as doxorubicin (DOX), 5'fluorouracil, etoposide, and Cisplatin, TM induces the unfolded protein response (UPR) by blocking aberrant glycosylation. Despite TM's antitumor effectiveness, its lack of cell-type specific cytotoxicity impedes its anticancer efficacy. Thus, various nanoencapsulation techniques and materials have been considered for use in experiments to reduce TM's cytotoxicity and improve efficacy as a targeted therapy. The current review is a profound audit of the benefits and pitfalls of TM in various cancers, focusing on breast, colon, and pancreatic cancers. Additional progressive studies have also discussed the use of TM in immune checkpoints and other unique pathways. Cytotoxicity and other possibly adverse effects of TM are highlighted based on the data from in vitro and in vivo assays. In addition, the recent advances in nano-based drug delivery systems regarding TM have been emphasized. However, the potential of this nucleoside inhibitor re-quires thorough investigation and research to determine its likeliness as a viable chemotherapeutic.

The active form of fingolimod (FTY720; FT) is a sphingosine-1-phosphate receptor agonist with potential ocular applications. The goal of the present study was to develop an FT-loaded nanoemulsion (NE; FT-NE) formulation for the efficient and prolonged delivery of FT to the posterior segment of the eye through the topical route. FT-NE formulations were prepared with homogenization followed by probe sonication method. The lead FT-NE formulation (0.15% and 0.3% w/v loading), comprising soybean oil as lipid and Tween® 80 and Poloxamer 188 as surfactants, was further evaluated for in vitro release, surface morphology, filtration sterilization, and stability at refrigerated temperature. The formulation, at both dose levels, showed desirable physicochemical characteristics, a nearly spherical shape with homogenous nanometric size distribution, and was stable for 180 days (last time point checked) at refrigerated temperature post-filtration through polyethersulfone (0.22 µm) membrane. In vitro release studies showed prolonged release, compared with the control FT solution (FT-S), over 24 h. The results from these studies demonstrate that the FT-NE formulation can serve as a viable platform for the ocular delivery of FT through the topical route.